June 20, 1955
SYNTHESIS OF IO-METHYL-3,4-BENZPYRENEAND S,IO-DIMETHYL-3,4-BENZPYRENE
[CONTRIBUTION FROM THE
LABORATORY OF ORGANIC
3297
CHEMISTRY OF THE UNIVERSITY O F KEW MEXICO]
The Synthesis of lO-Methy1-3,4-benzpyrene and S,lO-Dimethyl-3,4-ben~pyrene~-~ BY JULES L. ADELFANG4 AND GUIDOH.DAUB RECEIVED JANUARY 6, 1955 The Reformatsky reaction with 3-keto-1,2,3,1lb-tetrahydro-7H-meso-benzanthracene (117) followed by chain lengthe~iing via the Arndt-Eistert synthesis yielded (3-( 1,2,3,1lb-tetrahydro-7H-meso-benzanthrenyl-3)-butyric acid ( I X ) which upon cyclization gave 8-keto-l0-methyl-1,2,2a,5,8,9,10,1Oa-octahydro-3,4-benzpyrene (X). The ketone (X) was reduced by the Meerwein-Ponndorf method or methylated with methylmagnesium iodide producing carbinols which were dehydrated ant1 dehydrogenated t o lO-methyl-3,4-benzpyrene ( X I ) and 8,10-dimethyl-3,4-benzpyrene ( X I I ) , respectively. The over-all yield of each hydrocarbon from anthrone was approximately 9%. The new 3,4-benzpyrenes gave ultraviolet absorption spectra similar to the parent hydrocarbon, 3.4-benzpyrene. Samples of these new hydrocarbons are being evaluated for carcinogenic activity a t the Northwestern University Medical School, Evanston, Ill.
Nine of the possible twelve monomethyl-3,4- the endocyclic double bond (V) with the isomer obbenzpyrenes, namely, the 1’-,5a,5b 2’-,5aJc3’-,5a,5c tained in low yield probably having the exocyclic double bond (VI). 4’-,5d 2-,5e 5-,bf 6-,5fS-5g and 9-,5hmethyl-3,4-benzpyrenes, have been previously reported. CH, CHI This paper reports the synthesis of a tenth isomer, lO-methy1-3,4-benzpyrene (XI), as well as a new dimethyl derivative, 8,10-dimethyl-3,4-benzpyrene (XII) from readily available anthrone (I). Anthrone (I) was converted t o &(9,10-dihydro-9-anthrany1)-propionic acid (111) in 60% over-all yield using the procedures described by Daub and Doyle.6 Cyclization of the acid I11 with anhydrous hydrogen fluoride afforded an 87% yield of 3keto-1,2,3,11b-tetrahydro-7H-meso-benzanthracene (IV) previously reported by Cook, Ludwiczak and S~hoental.~ The hydroxy ester formed by the Reformatsky reaction of the ketone I V with ethyl a-bromopropionate was dehydrated with anhydrous formic acid VI1 and then hydrolyzed with dilute alkali to give a(l,llb-dihydro-7H-wzeso- benzanthrenyl-3) -propiAttempts were made first to lengthen the chain onic acid (V) in 77% over-all yield from the ketone of the unsaturated acid V using the Arndt-Eistert IV. Another acid, probably a-(1,2,3,llb-tetrahy- synthesis. Attempted rearrangement of what was dro-7H-meso-benzanthrylidene-3)-propionic acid probably the unsaturated diazoketone by prescribed (VI) was also isolated but in small quantities (less method^^-^^ failed to give tractable acidic material. than 2% yield). Attempts to prove the position of Catalytic hydrogenation of the unsaturated acid the double bonds in the two isomeric unsaturated V over Adams catalyst a t atmospheric pressure acids by oxidation experiments with potassium yielded a-(1,2,3,1lb-tetrahydro-7H-meso-benzanpermanganate or ozonolysis failed t o give identifi- threnyl-3)-propionic acid (VIII) as a highly viscous able products. oil. The acid chloride of VI11 prepared from the The ultraviolet absorption spectra of the two un- acid with phosphorus trichloride was allowed to saturated acids were measured and comparison of the react with an excess of diazomethane and the recurves with that of the known P-(1-methyl-1,llb- sulting diazoketone was rearranged in the presence dihydro-7H-meso-benzanthrenyl-3)-propionicacid of 95% ethanol and silver oxide.l0 Alkaline hy(VII)s showed the more abundant isomer to contain drolysis of the ethyl ester formed in the rearrangement gave p- (1,2,3,1lb-tetrahydro-7H-meso-benzan(1) From the thesis presented by Jules L. Adelfang t o the graduate faculty of the University of New Mexico in partial fulfillment of the rethrenyl-3)-butyric acid (IX) in an over-all yield of quirements for the M.S. degree. 787’ from the unsaturated acid V. This basic hy(2) This work was supported in part by a grant from the National drolysis was complete in one hour, indicating that Cancer Institute of the Naiiooal Institutes of Health, U. S. Public the hindering a-methyl group was not present in Health Service. (3) Presented before the Division of Organic Chemistry at the 127th Meeting of the American Chemical Society, Cincinnati, Ohio, hlarch 30-April 7, 1955, (4) Graduate Research Assistant, February, 1954, to August, 1954, ( 5 ) (a) W. E. Bachmann and M. Carmack, THISJOURNAL, 63, 2494 (1941); (b) G . A. R. Kon and E. M. F. Roe, J . Chem. Soc., 143 (1945); (c) L. F. Fieser and E. B. Hershberg, THISJOURNAL, 60, 1658 (1938); (d) L. F. Fieser and M. Fieser, i b i d . , 17, 782 (1935); (e) L. F. Fieser and H. Heyman, i b i d . , 63, 2333 (1941); (f) L. F. Fieser and E. B. Hershberg, i b i d . , 60, 2542 (1938); (9) J. M . L. Cameron, J. W. Cook, and R. Schoental, J . Chem. Soc., 257 (1952); (h) L F. Fieser and F. C. Novello, THISJOURNAL, 64, 1855 (1940). (6) G . H . Daub and W. C. Doyle, ibid., 74, 4449 (1952). (7) 3. W. Cook, R. S. Ludwiczak and R. Schoental, J . Chem. Soc., 1112 (1950). ( S ) 5. \V P a t t o n , l l a s t c r s Tlicsis, Uiiivrrsitp d New .Mexico, l ! G i ,
CH:,
I
1
LrI1I. R
=
COOH
(9) W. E. Bachmann and W. S. Struve, “Organic Rehctiuns,” Vol. I , John Wiley and Sons, Inc., New York, N. Y . , 1942, p. 38.
(10) M . S. Newman and A. S. Hussey, THIS JOURNAL, 69, 3023 (1017). ( 1 1 ) A . I,. \ V M s and A . 1,. A l e u l c r , J O r c . Chew , 13, 768 (llr48).
3298
JULES
L. ADELPANGAND GUIDOH. DAUB
Vol. 77
the acid IX and the Xrndt-Eistert synthesis had Samples of these hydrocarbons are being tested been successful. Complete saponification of the for carcinogenic activity a t Northwestern Univerunsaturated ester from the Reformatsky reaction in sity Medical School under the direction of Dr. D. which an a-methyl group was present required 32 Warren Stanger. hours. E~perimental~~ Cyclization of the acid I X with anhydrous hydrogen fluoride afforded S-keto-lO-methyl-l,2,2a,- p-(9,1O-Dihydro-9-anthranyl)-propionicAcid (111).-Ac3,8,9,10,10a-octahydro-3,4-benzpyrene(X) as a cording to a procedure previously describede 58.3 g. ( 0 . 3 mole) of anthrone (I) was converted t o 66.$ g. (87.55; yield) mixture of stereoisomers in 82% yield. of @'-(9-anthranyl)-propionic acid (II), m.p. 189-193', rePreparation of lO-methy1-3,4-benzpyrene (XI) ported m.p. 190-193". Reduction of this acid with sodium was accomplished by reduction of the ketone X and n-amyl alcohol gave 51.0 g. (7670yield) of p-(g,lO-diwith aluminum isopropoxide in isopropyl alcohol, to hydro-9-anthranyl)-propionic acid (111), m.p. 13X-140°, S -hydroxy - 10 - methy1-1,2,2a,5,S,9,10,10a - octahy- reported m.p. 139-140'. 3-Ket0-1,2,3,11b-tetrahydro-7H-nzeso-benzanthracene dro-3,4-benzpyrene which was directly dehydrated (IV).-Cvclization of 62.5 E. (0.252 mole) of 111 with 440 and dehydrogenated over palladium-charcoal a t ml. of anhydrous hydrogen fluoride was 'carried out in ;I 280-313'. The hydrocarbon XI was obtained in polyethylene beaker. After standing for two hours the exhydrogen fluoride was removed with a stream of nitrogen 16% over-all yield from the ketone X and formed a cess and the reaction mixture was poured on crushed ice. The dark purple picrate derivative. crude ketone was taken up in benzene and washed with water. Several extractions with aqueous sodium bicarbonate solution yielded no nncyclized acid. After drying over anhydrous sodium sulfate the benzene solution was passed through an alumina column. The benzene elutions were concentrated t o 100 ml. and upon addition of a n equal volume of petroleum ether (b.p. 70-90') 3-keto-l,2,3,11htetrahydro-7H-meso-benzanthracene ( I V ) crystallized as II I1 I I I1 bright yelloiv needles, m.p. 129.5-130.5', reported' m.p. 131-132', 51.6 g. (87c; yield). On standing for several months samples of the ketone became discolored and could s SI,R = H he purified by recrystallization from 95(%,alcohol with good S I I , R = CH:! recovery. Reaction of the ketone X with methylmagneThe Reformatsky Reaction on 3-Keto-1,2,3,1 lb-tetrahysium iodide gave 8-hydroxy-8, l@dimethyl-] ,2,za,- dro-7H-mcso-benzanthracene (IV).-Forty grams (0.17 mole) of the ketone I\- was dissolved in an anhydrous mix~ ~ s ~ 9 ~ 1 0 ~ 1 0 a ~ o c t a h ~ d r o ~ ~ 3 ~which 4 ~ b e nwas z ~ ~ rture e n eof 600 ml. of C.P. benzene and 600 ml. of C.P. ether it1 dehydrated and dehydrogenated over a palladium- a two-liter three necked flask equipped with ground glass charcoal catalyst a t 300-32~", affording 8,10-di- joints, fitted with a mercury sealed Hershberg stirrer, a conmethyl-3,1-benzpyrene ( ~ 1 1 )in over-all denser fitted with a drying tube, and a glass stopper. Initially the apparatus had been flame-dried and swept with yield. The hydrocarbon formed a dark brown nitrogen. Bfter the addition of 100 g. of amalgamated picrate derivative which could not be obtained zinc,'d 28 Inl.of ethJ-l a-bromopropionate (Eastman Kodak analytically pure due to the very low solubility of Co. 1041), and a trace of iodine, the mixture was refluxed for two days. An additional 100 g. of amalgamated zinc the parent hydrocarbon. and 28 ml. of ethyl a-bromopropionate were added after 17 The absorption lor 10-methyl- hours. The dark complex coated the sides of the flask and 3,4-benzpyrene (XI) and 8,lO-dimethy1-3,4-benzpy-caked the zinc during the second day. After standing at rene ( X I I ) , shown in Fig. 1 with the curve for 3,1- room temperature for two days the reaction mixture was with a solution of 20 ml. of concentrated 111-drobenzpyrene,i3 the presence of the par- hydrolyzed chloric acid in 200 ml. of water. The organic layer W I \ ent ring system in these new hydrocarbons. washed with water and sodium bicarbonate solution and dried over anhydrous sodium sulfate. Removal of the henzene-ether mixture under reduced pressure left a light red oil which was dehydrated with 540 ml. of anhydrous formic acid b y warming on a steam-bath for 15 minutes. 4.50 The formic acid \vas removed under reduced pressure and the remaining oil was refluxed for 32 hours with 56 g. of sodium hydroxide in 1.100 nil. of water. The alkaline solution wa5 filtered, extracted with a mixture of ether and benzene, and acidified yielding 46.5 g. (9Br; yield) of crude acidic material as a pink granular solid, m.p. 143-148'. The benzeneether extracts gave 0 . i 5 g. of recovered crude ketone ( I \ - ) . Two crystallizations of the crude acid from ethyl acetatc -x, afforded 28.0 g. of e-(1,11b-dihydro-7H-nwrso-benzanthrenyl3)-propionic acid (V), 1n.p. l.51.5-153°. A n additional 9.5 ..--...--. ,,,-B.n*r"'.n* g. of the acid \*, m.p. 148-153". was obtained from thc mother liquors to make the total yield 37..i g. ( 7 7 ( : ; ) . Repeated crystallization from ethyl acetate gave an analytical sample as almost colorlesq crystals, m.p. lt5l..5-15~3'. \;\ d n u l . Calcd. for CruHlaOt: C, 82.71; 13, 6 . 2 5 ; n e u t . . ,;, 1 equiv., 290. Found: C , 82.34; H , 6.20; neut. equiv., 287. 3.00 e 5 0 300 350 400 100 The methyl ester of \' was prepared with diazornethane. W.".l."QIh Irn"1, Crystallization from methanol gave methyl a-(1.1 lb-diFig. 1.-The ultraviolet absorption spectra of 3,4-betlz(13) All melting points are uncorrected. pyrene, 10-methyl-3,4-benzpyrene (XI) and X.10-dimethyl(11) Twenty mesh zinc ( J . 1'.Raker C.P.) was arnalganiated by Ll~r 3,4-berizpyrene (XII). CH ,
CH 3
I
-
377f
1
\/ ',I
--
(12) R. A. Friedel a n d M. Orchin, "Ultraviolet Spectra of Aromatic Compounds," John Wiley and Sons, Inc., S e w York. S. Y . . 1951, S o . .i34.
method described by Kolthufi a n d Sandell, "Textbook of QuanLitati!'e Inorganic Analysis," T h e XIacmillan Co., New York, N. Y . , 1948, IJ .;OR T h e freshly amalgamated zinc was washed with acetone and berizenc and stored under 1)enzene hefurc use
June 20, 1955
SYNTHESIS OF 10-METHYL-3,4-BENZPYRENEAND 8,10-DIMETHYL-3,4-BENZPYRENE 3299
-
-
hydro - 7H-meso benzanthrenyl - 3) propionate as colorless the benzene eluants yielded 2.0 g. (82y0)of 8-keto-10needles, m.p. 91.5-92.5'. methy1-1,2,2a,5,8,9,10,10a-octahydro-3,4-benzpyrene (X) as Anal. Calcd. for C21H2002: C, 82.85; H, 6.62. Found: a light yellow oil. Trituration of this oil with ether gave a solid which was crystallized from methanol giving the keC, 83.09; H , 6.54. tone X as a mixture of isomers, m.p. 140-155'. The mother liquors from the isolation of the acid V afAnal. Calcd. for CzlHzoO: C, 87.45; H, 6.99. Found: fordqd a second acid (0.65 g.), probably CY-( 1,2,3,llb-tetrahydro-7H-meso- benzanthrylidene-3)-propionic acid (VI), C, 87.28; H , 7.01. A sample of the mixture of isomeric ketones was converted m.p. 173-176'. An analytical sample was obtained, by reto the 2,4-dinitrophenylhydrazones. Crystallization twice peated recrystallization from ethyl acetate, as hard irregular from acetone gave a mixture of bright red needles and dark pellets, m.p. 177-178.5'. A.naZ. Calcd. for C20H1802: C, 82.74; H , 6.23; neut. red star-like crystals which had a diffuse melting point range higher than 220' accompanied by decomposition. equiv., 290. Found: C, 82.50; H , 6.07; neut. equiv., 288. Anal. Calcd. for C27H2404N4: C, 69.22; H, 5.16. Ultraviolet Absorption Spectra.-The ultraviolet absorpFound: C, 69.22; H , 5.35, tion spectra of the acids V and VI in 95cJc ethanol were lO-Methy1-3,4-benzpyrene(XI).-Reduction of 3.73 g. measured with a Model DU Beckman spectrophotometer. Maxima and (log e) values are: a-(l,llb-dihpdro-7H-meso- (0.013 mole) of the oily ketone X was carried out with 6.1 g. benzanthrenyl-3)-propionic acid (Y), 265 mp (3.90); a- (0.038 mole) of aluminum isopropoxide and 150 ml. of an( 1,2,3,1 l b - tetrahydro -7H meso - benzanthrylidene-3)-pro- hydrous isopropyl alcohol in a 250-ml. round bottom flask pionic acid (VI), 259 m p (3.95), 334 m p (3.68), and 349 m p fitted with a Hahn condenser.16 After 11 hours of slow distillation the distillate gave a negative test with 2,4-dinitro(3.60). a-( 1,2,3,11b-Tetrahydro-7H-meso-benzanthrenyl-3)-pro- phenylhydrazine reagent and the remainder of the isopropyl pionic Acid (VIII).-At atmospheric pressure, 10.15 g. alcohol was removed under reduced pressure. The reaction (0.035 mole) of a-1 ,llb-dihydro-7H-rneso-benzanthrenyl-3)- mixture then was treated with 20 ml. of concentrated hypropionic acid ( V ) , dissolved in 125 ml. of ethanol, was re- drochloric acid in 80 ml. of water and the yellow oil was taken up in benzene and washed with water. The benzene duced in the presence of 0.1 g. of Adams catalyst. After solution was dried over anhydrous sodium sulfate and the sol25 hours, a t room temperature, when 907, of the theoretical amount of hydrogen had been taken up, the solution was vent was removed under reduced pressure leaving 8-hydroxy 10-methyl - 1,2,2a,5,8,9,10, loa- octahydro - 3,4 - benzfiltered and the ethanol removed under reduced pressure. pyrene as a viscous oil. Last traces of ethanol were removed by the addition of benThe crude alcohol was dehydrated and dehydrogenated zene followed by further distillation. The highly viscous oil remaining, a-1,2,3,1 lb-tetrahydro-7H-meso-benzanthre- over 0.38 g. of 10% palladium-charcoal in an apparatus suggested by Fieser.'? The reaction was carried out in a nyl-3)-propionic acid (VIII), was a mixture of isomers which carbon dioxide atmosphere and the hydrogen evolved was could not be crystallized. p-( 1,2,3,11b-Tetrahydro-7H-meso-benzanthrenyl-3 )-buty- measured in a gas buret protected by an alkali trap. After about one-half hour a t 280-315', 55$& of the theoretical ric Acid (IX).-The crude reduced acid VI11 from above was dissolved in 85 ml. of anhydrous C.P. benzene and refluxed amount of hydrogen was given off. After cooling, the hard for two hours with 2.2 ml. (0.025 mole) of phosphorus tri- cake was pulverized in a mortar, dissolved in benzene, and chloride (J. T. Baker, C.P.). The solution of the acid chloride the solution filtered. The benzene solution was twice chromatographed through alumina and concentration of the was filtered and the benzene and excess phosphorus trieluants yielded 1.7 g. of lO-methyl-3,4-benzpyrene(XI), chloride were removed under reduced pressure. m.p. 170-175". Recrystallization from benzene-ethanol Diazomethane was prepared as described by Arndt15 in an all glass distilling apparatus fitted with two traps cooled to yielded 1.2 g. of minute yellow needles, m.p. 177-178". Chromatography and crystallization of the combined mother O", each containing 45 ml. of anhydrous ether. To the disliquors from benzene-methanol yielded an additional 0.4 g., tilling flask containing 80 ml. of 50% potassium hydroxide m.p. 178-178.5", making the total yield of 10-methyl-3,4and 270 ml. of ether, 25 g. of nitrosomethylurea was added. benzpyrene (XI) 1.6 g. (46% yield from X). An analytical The mixture was swirled and the diazomethane formed was sample prepared by crystallization from ethanol was obdistilled with the ether. The expected yield of diazomethtained as small yellow needles, m.p. 178-178.5'. ane was 6.5 g. (0.15 mole). Before use, the ether solution Anal. Calcd. for C21H14:C, 94.70; H , 5.30. Found: of diazomethane was dried over C.P. potassium hydroxide C, 94.75; H , 5.23. pellets for two hours a t 0 " . A picrate of X I was prepared using a saturated solution of The acid chloride prepared above was dissolved in C.P. picric acid in absolute ethanol. Crystallization of the picanhydrous benzene and added dropwise to the cold diazomethane solution. Evolution of nitrogen began immedi- rate from benzene yielded dark purple needles, m.p. 179.5180.5'. ately and continued for about one-half hour. After the reAnal. Calcd. for C2?H&hT~: C, 65.45; H, 3.46. action mixture was allowed to stand a t room temperature Found: C, 65.41; H, 3.09. for 45 minutes the ether was removed under reduced pressure. The remaining highly viscous, yellow diazoketone 8,IO-Dimethyl-3,4-benzpyrene(XII).-A Grignard rewas dissolved in 150 ml. of 95YGethanol and a t 65-70' was agent was prepared in the usual manner from 1.02 g. (0.042 treated with 1.5 g. of freshly precipitated silver oxide over mole) of magnesium and 6.4 g. (0.045 mole) of methyl ioa period of two hours. The copious evolution of nitrogen dide in 40 ml. of absolute ether. The oily ketone X, 4.03 ceased after one and three-quarters hours. The resulting g. (0.014 mole), dissolved in 30 ml. of ether and 20 ml. of ethanol solution of ethyl p-( 1,2,3,1lb-tetrahydro-7H-mesobenzene was added dropwise to the Grignard solution. benzanthrenyl-3)-butyratewas treated with norit and passed After standing a t room temperature for one hour the reacthrough an alumina column. The ethanol was removed tion mixture was hydrolyzed with 10 ml. of concentrated under reduced pressure and the red oily ester was refluxed hydrochloric acid in 40 ml. of water. The organic layer was for one hour with 175 ml. of t57c sodium hydroxide solution. washed with water and dried over anhydrous sodium sulfate. After one-half hour the insoluble sodium salt precipitated Removal of the solvent left 8-hydroxy-8,1O-dimethyl-l,2,2a,as a gummy mass. The salt was dissolved in hot water and 5,8,9,10,10a-octahydro-3,4-benzpyrene as a viscous yellow acidification yielded a red oil which was taken up in ether oil. and treated with norit. The ether solution was dried over The crude alcohol was dehydrated arid dehydrogenated anhydrous sodium sulfate and removal of the solvent yielded by heating with 0.4 g. of 107i8palladium-charcoal a t 300 8.4 g. (787, yield from \') of 8-(1,2,3,11b-tetrahydro-7H- 325' for one-half hour during which time 60Yc of the theomeso-benzanthrenyl-3)-butyricacid (IX) as a light red oil. retical amount of hydrogen was evolved. After cooling. 8-Keto-lO-methyl-l,2,2a,5,8,9,10,10a-octahydro-3,4-benzthe ha.rd cake was pulverized in a mortar, dissolved in a pyrene (X).-Cyclization of 2.6 g. (0.0090 mole) of large volume of boiling benzene, and the solution filtered to crude 8-( 1,2,3,1 lb-tetrahydro-7H - meso- benzanthrenyl-3)remove the catalyst. The crude hydrocarbon was chrobutyric acid ( I X ) was accomplished with 30 ml. of anhydrous matographed through an alumina column and concentration hydrogen fluoride. A benzene solution of the crude ketone (16) A. L. Wilds,"Organic Reactions,"Vol. 11, John Wiley and Sons, was passed through an alumina column. Concentration of
-
-
( 1 5 ) F. Amdt, "Organic Syntheses," Coli Vu1 11, Juhn Wiley and Suua. [ n c , S e w Yurk, N . Y , 1941, p. l o 5
Inc., New York, N. Y., 1944, p . 178. (17) 1.. P . Fiwer, "Experiments I U Orgauic Cheruibtry," Srcuud I>ditiuu, 1) C' H c d t h dud C u , W e n Vurk. N Y . . 19.11. y 462
:3:300
IRVING SCEIEER,
WILLIAM
1
