Nov. 20, 1955
cis- AND ~YU~S-CPDECALONE WITH DIAZOMETHANE [CONTRIBUTION FROM THE
DEPARTMENT OF CHEMISTRY,
5971
WASHINGTON UNIVERSITY]
Ring Enlargements. IV. Steric Influences in Diazomethane-Carbonyl Reactions. The Reaction of cis- and trans-a-Decalone with Diazomethane1a2 BY C. DAVID GUTSCHE AND HUGOH. PETER RECEIVED FEBRUARY 12, 1955 To study the steric influences in the diazomethane-carbonyl reaction, cis- and trans-a-decalone (I) have been investigated. The interaction of diazomethane with these compounds results in the formation of cis- and trans-a-hexahydrobenzosuberone (I1), cis- and trans-8-hexahydrobenzosuberone(111). the oxide I V and, under certain conditions, a hexahydrobenzocyclooctanone ( V ) . All of these compounds have been obtained in a state of known purity, either by synthesis or by isolation, and provide the basis for a quantitative assay of the product from diazomethane and compound I. By means of this assay, differences in the product ratios from the reactions involving cis-I and trans-I have been measured. Also, the effect of various reaction conditions have been investigated including changes in temperature, concentration, solvent and base.
In the reaction between cyclic ketones and diazomethane to produce ring-enlarged ketones and/or oxides, steric factors are undoubtedly important and may exert an influence at two stages of the reaction: the initial attack of the diazomethane a t the carbonyl group as well as the subsequent rearrangement of the resulting intermediate may be sterically-controlled. Examples of the first effect are the ring enlargements of 2-substituted cyclohexanones which, in many cases, proceed in lower yield than those involving cyclohexanones lacking 2-substituents. Thus, cyclohexanone yields 60-65% of cy~loheptanone,~ but 2-methylcyclohexanone gives and 2-cya 37y0 yield of methylcy~loheptanones,~ clohexylcyclohexanone is reported to yield only 4-570 of ring-enlarged ketone.6 Examples of the second effect are more difficult to establish, but the ratio of carbonyl product to oxide and the ratio of isomeric carbonyl products formed from unsymmetrically-substituted cycloalkanones may be determined, in part, by steric factors. For instance, the ratio of ketone to oxide is about 4 : 1 in the ring enlargement of cyclohexanone, but is closer to 1: 1 with 3,5,5-trimethylcyclohexanone. Also, in the latter example the two isomeric trimethylcycloheptanones are not formed in equal amount.6 I n all of these and similar examples, however, an electronic factor complicates the steric factor. Thus, alkyl groups are usually considered as electron-donating relative to hydrogen, and the lower reactivity of 2-alkylcyclohexanones might also be explained in terms of an inductive deactivation of the carbonyl group. Similarly, the decomposition of the intermediate might also be controlled by the greater electron-donating power of an RCHgroup over that of a CHZ- group. I n an attempt to study a system in which electronic differences are a t a minimum and in which steric differences should predominate, the present investigation was undertaken. One of the simplest systems in which this requirement appeared to be satisfied was that of the (1) This work was supported, in part, by grants-in-aid from the Monsanto Chemical Co. and the Office of Ordnance Research, Contract No. DA-23-072-ORD-767, and was presented a t the X I V t h International Union of Pure and Applied Chemistry, Zurich, Switzerland, July, 1955. (2) For paper I11 of this series cf. C . D. Gutsche end H. E. Johnson. THISJOURNAL, 77, 109 (1955). (3) E. P . Kohler, M. Tishler, H. Potter and H. T. Thompson, ibid., 61, 1057 (1939). (4) D. W. Adamson and J. Kenner, J . Chcm. SOC.,181 (1939). (5) M. Mousseron and G. Manon, Bull. SOC.chim. France, 392 ( 1 949).
( 6 ) M . Stoll and W. Scherrer, Hclv. C h i m . A d a , I S , 941 (1940).
cis- and trans-a-decalones, and it is with this pair of compounds that the present work deals. cis-cis-a-Decalol was synthesized in 50y0 over-all yield from a-naphthol by reduction with lithium-ammonia-ethanol' to 5,S-dihydro-1-naphthol followed by catalytic reduction to 5,6,7,8-tetrahydro-1-naphthols and then to a mixture of a-decalols from which the cis-cis isomer could be isolated as a solid. Oxidation with chromium trioxide-pyridineg gave 71% of pure cis-a-decalone (Ia). A mixture of a-decalols suitable for the preparation of the transketone could be obtained in 69% yield by the Raney nickel catalyzed reduction of a-naphthol'O or in 87% yield by a similar reduction of 5,6,7,8-tetrahydro-1-naphthol. Oxidation yielded a mixture of a-decalones which could be completely converted to trans-a-decalone by 12-hour refluxing with aqueous methanolic sodium hydroxide, the over-all yield from a-naphthol being 50%. One of the major obstacles to the interpretation of diazomethane reactions on the basis of the products isolated is the formation of difficultly-separable mixtures. The amounts of the various pure compounds isolated do not necessarily represent the amounts actually formed. For this reason it was important for the present investigation to find a method of assay which would provide an accurate estimate of all of the reaction products. Previously, the method of quantitative infrared analysis had been successfully employed in a similar study" and it was again chosen as the most appropriate. For this method, however, i t was necessary to secure pure samples of the hitherto unknown cis- and transa-hexahydrobenzosuberone (11), cis- and trans-@hexahydrobenzosuberone (111) and the oxide IV. Catalytic reduction of a-benzosuberone in the presence of Adams catalyst followed by oxidation of the product gave a 44% yield of 11. (7) Cf. A. L. Wilds and N. A. Nelson, TEXISJOURNAL, 75, 5360 (1953). ( 8 ) This material, obtained in 90% yield, previously has been prepared from a-naphthol in ca. 407, yield by catalytic hydrogenation and in ca. 85% yield by chemical reduction. The present method has the advantage over earlier procedures both with respect to yield and t o ease of manipulation. (9) G. I. POOS, G. E. Arth. G.E. Beyler and L. H. Sarett. THIS JOURNAL, 7 6 , 422 (1953). (10) As has been observed by H. E. Ungnade and co-workers, ibid., 66, 118, 1218 (1944), and by others, the extent of hydrogenolysis can be reduced by addition of base to the hydrogenation reaction mixture. It was also observed in the present case that when larger amounts of base were added, the amount of a-decalol formed was greatly reduced, the major product being 1,2,3,4-tetrahydro-l-naphthol (70%). (11) C. D . Gutsche. THISJ O U R N A L , 71, 3513 (1949).
5972
C. DAVIDGITTSCIIR AND HITGO H. PETER
Vol. 77
0
0
To test the reliability of the method a two-component mixture and a four-component mixture of known composition were assayed with the following results: A mixture known to contain 38.8% of Ia and 61.2% of I b gave values of 39% and 61% Ia (cis) IIa (cis) upon infrared analysis; a mixture known to conIh ( t r a n s ) IIb (trans) tain 8% of IV, 16% of IIb, 26% of IIb and 50% of I b gave values of 8, 12, 30 and 50%. It is probably safe to assume, therefore, that the absolute error in the values reported in Tables I-IV is not more than =t5y0and in many cases, less. The reactions with diazomethane were carried out in two ways, designated as the ex situ and the in situ methods. The former refers to those reactions IIIa (cis) IV T‘ IIIb (trans) in which an ethereal solution of diazomethane is en]The pure cis isomer was obtained via the semicarba- ployed, while the latter refers to those reactions in zone and it is interesting to note in this respect that which N-nitrosomethylurethan is added to a basic IIa shows much less tendency to isomerize to I I b solution containing the ketone. Inspection of Tables I11 and IV reveals that under comparable conthan does its six-membered analog Ia to I b ; thus, ditions in the ex situ method, trans-a-decalone hydrolysis of the semicarbazone of IIa proceeds with shows a much greater tendency to form the oxide little, if any, inversion of configuration. Similarly, than does cis-a-decalone, the ratio of ketone to catalytic reduction of a-benzosuberone in the pres- oxide being about 1.5-2.0 and 20 (or greater), reence of Raney nickel, oxidation of the product, spectively, A similar difference has been reported treatment of the crude ketone with aqueous meth- for an ex situ reaction with the 17-epimers of 17anolic sodium hydroxide and purification via the formyl-4-androsten-17-0l-3-one (VIII) which yields semicarbazone yielded the pure trans isomer IIb. a ketone (3oyO) from the a-isomer and the oxide Catalytic reduction of p- (2-carboxyphenyl)-pro- (33%) from the P-isomer.13 Under in situ condipionic acid in the presence of Adams catalyst gave tions, also (cf. Tables I and 11) the trans isomer I b an 87% yield of cis-p-(2-carboxycyclohexane)-pro- forms more oxide than the cis isomer Ia, the ketone pionic acid (VIa) which could be isomerized to the to oxide ratios being about 1.5 and 7, respectively. trans isomer VIb by heating a t 200’ with concen- The latter value is lower than in the ex situ case due trated sodium hydroxide. The cis and trans isomers to the base-catalyzed inversion of Ia to I b during the of VI were subjected to bis-homologation via the OH CHO Arndt-Eistert method to yield the cis and trans isomers of y-(2-carboxymethylcyclohexane)-butyric I ,XHO ,,OH acid (VII). Cyclization by pyrolysis of the corresponding thorium salts then provided the cis and trans isomers of P-hexahydrobenzosuberone (111).
I
/\./C02H ~
0 ----f C O H --, ,J‘(
VIa I
/COzH COiH
OL/ VIb
r’
/-COIH 2
~ --f IIIa
VIIIa
-n
/-COzH r C O > H + IIIb
It was not possible to isolate a pure sample of the oxide IV. However, it was possible to secure its infrared spectrum by virtue of the fact that the composition of the mixture of IV and Ib (obtained from a diazomethane reaction) could be determined via infrared analysis for I b and chemical analysis for IV. The infrared spectrum of the oxide could thus be obtained by difference and it, along with the spectra of the six ketones described above, provided the necessary data for the analysis of the products from diazomethane and the a-decalones. The analysis of the reaction mixture by means of iiifrared followed well-established procedures.12 (12) C f
in situ reaction, a rearrangement which, it should be pointed out, does not occur under ex situ conditions. The oxide formed from I a was shown, in fact, to be derived from Ib (hydrolysis to the glycol IX followed by periodate oxidation to Ib). The glycol IX from I b was further characterized by acid-catalyzed rearrangement to decahydro-l-naphthylcarboxaldehyde14 from which the known tmnc -transCHZOH
VIIb
frrr emtriple, ?I 0 &Tellon “Analytical Ab5orption Spec, K r w Vork N V , 1950.
l r o ~ ~ o p’ yJ.) I , Riizicka a r i i l IY. llriiggrr, IIdP. Chiin. Arrci. 9. :iR9 ( 1 9 2 6 ) .
Nov. 20, 1955
BENZO [c]PHENANTHRENES
5977
IX described above was refluxcd for 20 niiiiutes with 20 ml. of 20% sulfuric acid. Several evaporative distillations of the product yielded a very viscous oil, b.p. 130-140° (0.02 mm.), n 2 5 ~ 1.5150. Anal. Calcd. for C22H3.502: C, 79.46; H, 10.92. Found: C, 78.85; H, 10.75. Prolonged refluxing of the above material with 2,4-dinitrophenylhydrazine hydrochloride in ethanol yielded the 2,4 - dinitrophenylhydrazone of trans - trans-decahydro -1naphthylcarboxaldehyde, m .p. 170-171.5’. Infrared Analysis.-The quantitative infrared analyses were carried out in carbon disulfide solution in 0.1-mm. thick cells. A Perkin-Elmer model 21 double-beam instrument was used without compensation for the solvent, and corrections for solvent absorption were applied to the calculations. Sr. LOUIS,~ I I S S O U R I
The pure 2,4-dinitrophenylhydrazone was converted to the ketone by the procedure of Martin and Demaeker . 8 6 The crude ketone was evaporatively distilled a t 45-55” (0.03 mm.) and obtained in 83% over-all yield as a colorless Oil. n3’D 1.4974. Anal. Calcd. for Cl2HloO: C, 79.94; H, 11.18. Found: C, 79.44; H, 11.22. The semicarbazone of V was obtained as small, colorless needles after recrystallization from ethanol; m.p. 201-202 dec Anal. Calcd. for C I ~ H ~ ~ X ~C,O :65.78; H, 9.77. Found: C, 65.73; H, 10.14. 2-( Decahydro-1-naphthyl)-octahydrospiro[ 1,3-dioxolane4,1’(2’H)-naphthalene] (X).37-A 2.0-g. sample of the glycol -
.
(36) R. H. Martin and J. Demaeker, Nature, 173, 266 (1954). (37) We are indebted t o Dr. Leonard T. Capell of Chemical Abs t i a c l s for information concerning the nomenclature of this compound.
~[CONTRIBUIIOY FROM
THE
BAKERLABORATORY OF CIIBMISTRY, CORNELI UNIVERSII L]
Polynuclear Aromatic Hydrocarbons. 1V.I Benzo [clphenanthrenes B Y DONALD D. PHILLIPS AND A. WILLIAM JOHNSON RECEIVED JUNE9, 1955
A new method for the preparation of benzo[c]phenanthrene derivatives has been developed. Advantage is taken of the polyfunctional nature of the readily available P-methallylsuccinic anhydride ( I ) which, when treated uith benzene in the Friedel-Crafts reaction, gives rise to keto acids I1 and 111, both of which may be converted in good over-all yield to the genadimethyl derivative XIII, and thence to 5-methylbenzo[c]phenanthrene(XVIII). Compounds analogous to XI11 are of interest as potential carcinogenic agents and may prove useful in establishing the role of coplanarity in carcinogenesis among polynuclear aromatic hydrocarbons.
One of the most intriguing problems in the study be carcinogenic6 and suitably substituted benzo[c]of carcinogenic hydrocarbons has been the corre- phenanthrenes are non-planar because of steric inlation between chemical structure and biological terference between carbons 1 and 12.’ These activity. Numerous theories have been published2 would be particularly interesting to examine for on this subject but as yet none has been found activity because they still possess the important8 satisfactory in all respects. 0,lO-phenanthrene double bond which was absent Although coplanarity has been suggested as a in most of the reduced hydrocarbons previously requirement for carcinogenic activity, the impor- t e ~ t e d . ~ , ~ tance of this structural feature per se has not been Several synthetic routes to the benzo [clphenanfully investigated. Badger* has found that partial threne ring system have been reported in the recent hydrogenation of several carcinogenic hydrocarbons literature10s16 but none of them seemed practical for destroys their activity and has ascribed this to a preparing both the hindered and partially reduced disruption in the coplanarity of the molecule. The derivatives that we wished to investigate. Morerecent important discovery by Miller5 that 3,4- over, we hoped to devise a synthesis based on readbenzpyrene is rapidly bound to protein in the epi- ily available starting materials so that a variety of dermal fraction of mouse skin indicates that some substituted benzo[c]phenanthrenes could be exkind of complex formation takes place and the rela- amined. In this respect, @-methallylsuccinic antive importance of coplanarity in this reaction takes hydride (I) seemed eminently suited to our purpose on added significance. because of its polyfunctional nature and ease of As one approach to this problem we have se- preparation from maleic anhydride and isobutyllected for study the benzo[c]phenanthrene (cf. ene.” When condensed with benzene in the presXVIII) ring system. Our choice was based on (6) Reference 2, p. 86. the fact that several of its derivatives are known to F. H . Herbstein and G. M. 1. Schmidt, 3. Chem. Soc., 3302 (1) Paper 111, D . D. Phillips and E. J. McWhorter, THISJOURNAL, 77, 3856 (1955). (2) For an excellent review on the subject of chemical constitution and carcinogenic activity see G. M. Badger in “Advances in Cancer Research,” Vol. 2, Academic Press Inc., New York, N. Y . , 1954, pp. 73-127. (3) (a) Reference 2, p. 98. (b) Coplanarity is an important feature in the currently popular “electron density hypothesis” theory as applied t o carcinogenic hydrocarbons; see A. Pullman, A n n . chim., 2, 5 (1947); P. Daudel and R . Daudel, B i d . m i d . , 39, No. 4, 1 (1950), and ref. 2, p. 101. (4) G . M. Badger, Brit.J . Caxcer, 2 , 309 (1948). (5) E. C. Miller, Canccv Research, 11, 100 (1951). F o r proof that the binding is covalent in nature see P . M . Bhargava, H. 1. Hudler and C. Heidelberger, T H I S JormNAi,, 77, 2877 (1955).
(7) (1954); M. S.Newman and W. B. Wheatley, THIS JOURNAL, 70, 1913 (1848). (8) R. Robinson, Brit. M c d . J., I , 943 (1946); ref. 2 . pp. 95-97. (9) M . J. Shear, A m . J . Cancer, 28, 334 (1936); 33, 439 (1938); J. L. Hartwell, “Survey of Compounds which Have Been Tested for Carcinogenic Activity,” 1st and 2nd Ed., Public Health Service Publication, Washington, D . C., 1940 and 1951. (10) M. S. Newman, H. V. Anderson and K. H. Takemura, THIS JOURNAL, 76, 347 (1953); J. Szmuszkovicz and E. J. Modest, ibid., 7 0 , 2542 (1948); 72, 566 (1950); C. Djerassi and T . T . Grossnickle, ibid., 76, 1741 (1954); A. L.Wilds and R. G. Werth, 3. Org. Chem., 17, 1154 (1952); S. M. Mukherji, V. S. Gaind and P. N. Rao, ibid., 19,328 (1954); G.T. Tatevosyan and V. 0. Bahayan, J . Cen. Chcm. 2 2 , 1421 (1952). (11) K. Alder, F. Pascher and A. Schmitz, Be?., 76B,47 (1943).
