[CONTRIBUTION FROM THE UNITEDSTATES DEPARTMENT OF AGRICULTURE, AQRICULTURAL RESEARCH ADMINISTRATION, BUREAUOF ENTOMOLOGY AND PLANT QUARANTINE]
CONSTITUENTS OF PYRETHRUM FLOWERS. XVIII. T H E STRUCTURE AND ISOMERISM OF PYRETHROLONE AND CINEROLONE F. B. LAFORGE AND W. F. BARTHEL Received January 17, 1945
Pyrethrolone, the cyclopentenolone component of the pyrethrins, formerly considered to be a homogeneous compound, has recently been shown to be a mixture of several related compounds, and the isolation of the semicarbazones of five of its constituents has been described (1). Although these semicarbazones do not differ markedly in melting point and solubility, their acetyl derivatives exhibit wide differences in these respects, which permit their ready isolation. Three of the semicarbazonesare represented by the empirical formula C12H17N302, the other two by CllH17NS02. The corresponding keto alcohols of the first group, of formula CllH1402,have been temporarily designated as pyrethrolones B-1, B-2, and C, those of the second pair, of formula ClOK14O2, as pyrethrolones A-1 and A-2. The semicarbazones and acetyl semicarbazones having been characterized, a series of other derivatives of each of the pyrethrolone components have now been prepared for further comparative study. The semicarbazones of pyrethrolones B-1 and B-2 were hydrogenated to the tetrahydrosemicarbazones, which were hydrolyzed to the free tetrahydropyrethrolones. The hydroxyl group was substituted by chlorine, and the chloro derivatives were reduced to the desoxy compound, tetrahydropyrethrone (dihydrojasmone). The free pyrethrolones were also regenerated by hydrolysis of their semicarbazones and reconverted to the acetyl derivatives and acetyl semicarbazones. These reactions are all well known, having been applied to crude “pyrethrolone” as originally obtained. Each derivative of pyrethrolone B-1 prepared from the acetyl semicarbazone (m.p. 133”) was compared with the corresponding one prepared from the acetyl semicarbazone of pyrethrolone B-2 (m.p. 175”). The outstanding difference between the derivatives of the two series w a ~ found to relate to optical activity. All compounds derived from pyrethrolone B-1, insofar as they possess an asymmetric center at carbon 5 in formula I (2), are optically active ; those from pyrethrolone €3-2 are optically inactive.
0 H
I 114
STRUCTURE OF PYRETHROLONE AND CINEROLONE
115
The acetyl semicarbazone B-1 as originally isolated (m.p. 133-135") is strongly Optically active, f a ] D +49". The tetrahydrosemicarbazone obtained by hydrogenation of the semicarbamne is identical with the known optically active derivative melting a t 198". The free tetrahydropyrethrolone is optically active, [a],, +13.5", but the tetrahydropyrethrone, formula 11, obtained via the chloro compound by reduction, is inactive and identical with dihydrojasmone, 11.
CH,
I
H
O
H2
-
CHn
I1
Pyrethrolone B-1, obtained by hydrolysis of the semicarbazone, is optically active but to a less degree, [& +11.7", than has been reported for heterogeneous pyrethrolone. The semicarbazone of the acetyl derivative of this regenerated pyrethrolone melts indefinitely a t about 146", and it can be separated into two components by extraction with benzene. One of these melts at 131-132" and is identical with the acetyl semicarbazone of pyrethrolone B-1. The other melts a t 175-176" and is identical with the semicarbazone of acetylpyrethrolone B-2. Racemization has therefore occurred during hydrolysis. Starting from the original semicarbazone of acetylpyrethrolone B-2 (m.p. 173-175"), the same derivatives were prepared as of the B-1 series and their respective properties compared. The semicarbazone itself is optically inactive. The tetrahydro semicarbazone melts a t 172-173" and is identical with the racemic tetrahydropyrethrolone semicarbazone described in a previous article (3). The chloro compound was prepared from the free tetrahydropyrethrolone, reduced to tetrahydropyrethrone (dihydrojasmone), and identified by comparison of its derivatives with the corresponding ones of the preceding series. The free pyrethrolone obtained by hydrolysis of the semicarbazone B-2 is optically inactive. The semicarbazone of its acetyl derivative (map. 174-176") is homogeneous and identical with the original compound. Each derivative of the B-1 series agreed within experimental error with the corresponding one of the B-2 series with respect to refractive index (in the case of liquids), elementary analysis, and the results of terminal-methyl determinations. The importance of the last-mentioned results will be emphasized later. From the data presented it is now possible to offer an explanation of the nature of the two isomeric pyrethrolones, B-1 and B-2, and their relation to the heterogeneous "pyrethrolone" as previously known. Pyrethrolone B-1 is the optically active and B-2 the racemic mixture. Both are present in "pyrethrolone", as ordinarily prepared by hydrolysis of the crude semicarbazone, in varying amounts depending upon the conditions of the reaction, which is always accompanied by more or less racemization (3). Therefore, various specific rotation values have been reported. When all the constituents of pyrethrolone are acetylated, the
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F. B. LAFORGE AND W. F. BARTHEL
products can be fractionated with elinhation of lower-boiling components and a fraction obtained consisting of the acetyl derivatives of both the active and the racemic acetylpyrethrolone. By a fortunate circumstance the corresponding semicarbazones exhibit different solubilities permitting their separation. Pyrethrolone C must be considered as a mixture of both the active and the partly racemized compound, from which the constituents of lower molecular weight have been eliminated. Hence all three forms are to be represented by the same formula, I, which is in accord with the spectrographic results indicating the presence of two chromophores. It will be observed in the experimental part that most of the terminal-methyl values exceed those theoretically required by the compound of formula I and its derivatives, whereas from analogy the methyl group in position 3 in the nucleus should give less than the theoretical value. All preparations of pyrethrolone and of the corresponding semicarbazones gave values about 10% above the theoretical but really about 20% higher than would be expected. There is thus an indication of the presence of some related form, possibly dihydropyrethrolone of structure 111,which would provide an explanation of the observed excess of terminal-methyl content. CH3 H2())C-C-C=C-CH3 Hz Hz H H
H--
0 0
H
I11 However, the much higher terminal-methyl values observed on lower-boiling fractions obtained by fractionation of crude heterogeneous pyrethrolone are due to a concentration in them of a compound of boiling point and molecular weight lower than those of pyrethrolone. By repeated fractionation this component can be isolated, although only in small amount, almost free of the main constituents. Now that its properties are known, it is apparent that a fraction previously obtained, and designated 1-A (2), must have consisted almost entirely of this constituent. It is readily obtained in comparatively large quantities by fractional distillation of acetylated pyrethrolone, and is isolated by conversion to the acetyl semicarbazone. As in the case of the semicarbazone of acetylpyrethrolone, two isomeric forms having different solubilities and different melting points were observed. The corresponding free keto alcohol contains one carbon atom less than does pyrethrolone, one more terminal-methyl group, and only two unsaturated linkages. The spectrographic data furnished by the free ketone reveal the presence of only one chromophore. From its properties and behavior and its analogy to pyrethrolone it has been assigned formula IV, and with reference to its plant source, Chrysanthemum cinerariaefolium, it is named (‘cinerolone.” The name “pyrethrolone” should be retained for the compound of formula I.
STRUCTURE OF PYRETHROLONE AND CINEROLONE
117
CH3 HZ(fC-C=C-CH3 Ht H H H--0
0 H IV The relation to each other of the two isomeric cinerolones, previously designated as “pyrethrolones” A-1 and A-2, was also established by a comparison of a series of derivatives of each form. Acetylcinerolone semicarbazone A-1 is optically active, [ a ]+50°, ~ as is the free cinerolone. Cinerolone proved to be sufficiently stable to permit direct substitution of the hydroxyl group with chlorine by treatment with thionyl chloride. The resulting chloro derivative was then reduced to the optically inactive desoxy compound, cinerone, of formula V. CH,
v The semicarbazone and p-nitrophenylhydrazone were prepared from the free ketone. Cinerolone A-1 was reconverted to the acetyl semicarbazone, which melted a t 146’. It could be separated into two fractions by extraction with benzene, but the quantities of material available were too small for complete purification of the fractions. . Acetylcinerolone A-2 showed only a trace of optical activity, due probably to an impurity. The free cinerolone was inactive. The chloro compound prepared directly from it was reduced to the desoxy compound, which furnished a semicarbazone identical with the one from the active isomer. Cinerolone A-2 is therefore the racemic modification. Cinerolone, which is more stable than pyrethrolone, was also obtained by heating the lower-boiling fraction of pyrethrolone or acetylated pyrethrolone with maleic anhydride. This reagent reacts with pyrethrolone to form polymerization products insoluble in most solvents. By extraction with methanol and saponification the cinerolone can be obtained, but only in small yield. EXPERIMENTAL
Derivatives of pyrethrolone B-1 and B-2. Since all the derivatives of pyrethrolone B-1 and B-2 were prepared by methods that have already been described, only such physical constants and analytical data as have a bearing on the relations of the two isomers need be reported.
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F. B. LAFORGE AND W. F. BARTHEL
The pyrethrolones were obtained by hydrolysis of their respective semicarbazones. Pyrethrolones: B-1 [a]: +11.7', in ethanol, n: 1.5424;B-2 [aID0', n: 1.5391. Anal. Calc'd for CI1HI402:1 CH3, 8.4. Found for B-1: CH3, 8.9, 9.2; for B-2: CHI, 9.2, 9.4. Semicarbazones regenerated from pyrethrolones B-1 and B-2: B-I, m.p. 219"; B-2, m.p. 208'9 [&ID 0". Anal. Calc'd for C1~Hl,N302:1 CH3, 6.4. Found for B-1 : CH3, 7.0,7.2. Tetrahydropyrethrolone semicarbazones (3) (by hydrogenation of original semicarbazones): B-1, m.p. 198', B-2, m.p. 172-173", [.]I, . ' 0 Anal. Calc'd for C ~ ~ H Z ~ N2CH3, ~ O Z12.5. : Found for B-1: CHs, 11.9, 12.1; for B-2: CH3, 11.3, 11.1. Tetrahydropyrethrolones: B-1, [a]: +13.5", in ethanol, n t 1.4905, n: = 1.4900; B-2, [ a ] D o", 1.4892. Anal. Calc'd for CllHls02: 2CH3, 16.4. Found for B-1 : CH3, 14.3,14.6. 5-Chlorotetrahydropyrethrones: B-1, ng 1.4897; B-2, n: 1.4885. And. Calc'd for CllH1&IO: C1, 17.7. Found for B-1: C1, 18.1, 18.2, 18.0; for B-2: C1, 18.1, 18.2. Tetrahydropyrethrone: B-1, [ a ] D O", ng 1.4767; B-2, n: 1.4757. Tetrahydropyrethrone semicarbazones : B-I, m.p, 176-177'; B-2, m.p. 176-177'. Both compounds also melted a t this temperature when mixed together or with authentic dihydrojasmone. The p-nitrophenylhydrazones of tetrahydropyrethrones B-1 and B-2 melted separately and in mixture a t 116-117", which is higher than reported in a previous article (3). This derivative had a t that time been prepared from tetrahydropyrethrone originating from heterogeneous pyrethrolone. Acetyl pyrethrolone regenerated from pyrethrolones B-1 and B-2: B-I, n: 1.5145; B-2, n: 1.5125. Anal. Calc'd for C18HleOs: C, 70.88; H , 7.32; 2CH3,13.6. Found for B-1 : C, 70.60; H, 7.45; CH3,13.0,14.2; for B-2: CHs, 14.3,14.4. Acetyl semicarbazone from regenerated pyrethrolones B-1 and B-2: B-1 was separated into a benzene-soluble fraction (m.p. 131') and an insoluble fraction (m.p. 176-176") after recrystallization from ethyl acetate; B-2, m.p. 174-176". Anal. Calc'd for C1,Hl0N3O3:2CH3, 10.8. Found for B-I: Fraction m.p. 131", CH3, 10.3; Fraction m.p. 175", CH3, 10.7; for B-2; CH3, 10.8. Derivatives of cinerolone A-1 and A-1. Cinerolone A-1 was prepared by agitating 3 g. of its semicarbazone (m.p. 202-204') with a saturated aqueous solution of potassium bieulfate in the presence of peroxide-free ether. The free ketone was isolated in the usual manner and distilled between 120" and 124' (p = 1-2 mm.). The yield waa 1.7 g. [a]: +9.9" in ethanol, n: 1.5210,Xmax. = 2275, E = 15,500. Cinerolone A-2 was prepared in the same manner: [aID ,'O n: 1.5240. Anal. Calc'd for CloHl4O2:C, 72.29; H, 8.45; 2CHs, 18.1 Found for A-1: C, 71.66; 71.69; H, 8.69, 8.76; CH3, 15.0 15.1; for A-2; C, 72.44; H, 8.69. Semicarbazone regenerated from cinerolone A-1 (m.p. 201-203"). A n d . Calc'd for CllH1?N302: 2CH3, 13.4. Found: CH3, 11.1, 10.9. Acetylcinerolone A-1 was prepared from cinerolone A-1 by the process employed for the preparation of acetylpyrethrolone. One and four-tenths grams of cinerolone yielded 1.3 g. of distilled product, ng 1.4965. Anal. Calc'd for C12HleOs: C, 69.21; H, 7.74; 3CHs, 21.6. Found: C, 69.33, 69.65; H, 7.81, 8.16; CH3, 17.9,lg.l. Acetylcinerolone semicarbaeone from acetyl cinerolone A-1 (m.p. 146-147").
STRUCTURE OF PYRETHROLONE AND CINEROLONE
119
A n a l . Calc'd for ClaHlgN3Os: 3CH3, 17.0. Found: CH,, 14.2, 14.5. 11was separated into two fractions by extraction with benzene. The insoluble part melted a t 150" and the soluble part a t about 146", but the quantities were too small for complete purification. 6 Chlorocinerone A-2. One gram of cinerolone was cooled to below O", and 1 ml. of cold thionyl chloride was added gradually. After the evolution of hydrochloric acid had subsided, 0.3 ml. more of the reagent was added and the reaction was allowed to proceed for about 20 minutes a t room temperature. Water and cracked ice were added, and the red reaction product was extracted with petroleum ether. The solution was washed with water and with dilute sodium bicarbonate solution, and then dried. The solvent was removed by evaporation, and the residue distilled a t about 2 mm. pressure. The boiling poirt, around SO", was not accurately determined. The yield was 0.8 g., n; 1.5105. (5Chlorocinerolone -4-2 was prepared in the same manner, n: 1.5148.) A n a l . Calc'd for CloHlsCIO:C1, 19.24. Found for A-1 : C1,19.60,19.15. Cinerone. One gram of 5-chlorocinerone A-1 was dissolved in about 6 ml. of acetic acid, and 2.5 g. of zinc dust was added in small portions. The reduction proceeded with evolution of heat and was completed by warming for a short time on the steam-bath. Water was added, and the reduction product was extracted with petroleum ether. The solution was washed free from acid with water and sodium bicarbonate solution, and after removal of the solvent the product was distilled under a moderate vacuum. Cinerone has a pleasant odor resembling dihydrojasmone, [aIDO', n: 1.4978. (5-Chlorocinerone A-2, by the same process yielded cinerone, n; 1.5067.) Semicarbazones of cinerone A-1 and A-2. These derivatives were prepared in the usual manner and recrystallized from methanol. The products from both sources melted a t 214-215", as did a mixture of both. ilnal. Calc'd for CllHllNaO: C, 63.77; H, 8.21; N, 20.2; 2CHa, 14.5. Found for A-1: C, 64.27; 63.69, 63.96; H, 8.19, 8.35, 8.51: N, 19.53, CH3, 11.9, 12.8; for A-2; C, 64.03, 64.31; H, 8.25, 8.47. The p-nitrophenylhydrazone of cinerone A-1 was prepared by mixing a methanol solution of cinerone with a n aqueous solution of the equimolecular quantity of p-nitrophenylhydrazine hydrochloride. The derivative crystallized in red prisms. It was recrystallized from methanol and melted at 148". A n a l . Calc'd for C l ~ H l ~ N a C, O ~67.36; : H, 6.66; N, 14.73. Found: C, 67.05,67.31; H, 6.73,6.78; N, 14.36. The corresponding derivative from cinerone A-2 melted a t 140-142'. Pyretholone C. Sixteen grams of "pyrethrolone," prepared through the usual steps from pyrethrin semicarbazone that had been recrystallized from methanol, was separated by distillation into 7.9 g . of fraction 1 (n: 1.53.18, CH,, 10.45,10.95) and 4.25 g. of fraction 2 (n: 1.5390, CH3, 8.74, 8.84). Fraction 1 was acetylated, and the acetylated product fractionally distilled, yielding 2.9 g . of a low-boiling fraction (n: 1.4988; CH3,17.55,17.50). The semicarbazone prepared from this material was separated by differential solubility in benzene into 2.2 g. of soluble and 0.8 g. of insoluble constituents melting at 147-148" and 155', respectively. A n a l . Calc'd for ClaHlsN303: 3CH3, 17.0. Found for soluble fraction: CHI, 15.2, 14.3; for insoluble fraction: CHa, 14.0, 14.2. The lowest-boiling fraction of acetyl derivatives therefore consists for the greater part of acetylcinerolone. The pyrethrolone fraction 2 yielded 4 g. of acetyl derivative (n: 1.5119, CHB, 13.8,13.8), from which the semicarbazone was obtained as a mixture of the optical isomers. These were separated with benzene into 0.9 g. of the insoluble racemic form (m.p. 170°, CHa, 11.2, 11.01 and 2.3 g. of the soluble dextro form (m.p. 132-134"; CHs, 10.5, 10.6, calc'd, 10.8).
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F. B. LAFORGE AND W. F. BARTHEL
Fraction 2 therefore contains no appreciable amount of cinerolone, but is a mixture of the two forms of pyrethrolone. SUMMARY
Pyrethrolone, as prepared by hydrolysis of the semicarbaaone, is a mixture the greater part of which consists of the dextro and racemic forms of the compound of the empirical formula CllH1402and structure I. Another constituent present in lesser amount, also in the dextro and racemic forms, has the composition CloHl4O2and structure IV. This constituent has been named “cinerolone’:. These structures have been confirmed by the preparation and comparison of the properties of a number of derivatives of each of the constituents. BELTSVILLE, MD. REFERENCES
(1) LAFORGE AND BARTHEL, J . Org. Chem., 10, 106 (1945). (2) LAFORGE AND BARTHEL, J . Org. Chem., 9,242 (1944). A N D HALLER, J . Am. Chem. SOC., 68,1777 (1936) (3) LAFORGE
