Aug. 20, 1952
S Y N T H E S I S OF
[CONTRIBUTION FROM
THE
4089
2-METHYL-1,4-NAPHTHOQUINONE-4-C'4
DEPARTMENT OF BIOCHEMISTRY,ST.LOUIS UNIVERSITY SCHOOLOF MEDICINE ]
Synthesis of 2-Methyl- 1,4-naphthoq~inone-4-C~~' BY LUNG LPsb AND WILLIAMH. ELLIOTT~ RECEIVED FEBRUARY 22, 1952 A new synthesis of the vitamin K substitute, 2-methyl-1,4-naphthoquinone, has been developed and used t o incorporate carbon-14 into the 4-position of this compound. T h e reaction sequence has been used successfully t o prepare the quinone in an over-all yield of 25% based on the isotopic carbon dioxide using 5 mM. of barium carbonate-C14 of activities of 1 pc., 100 pc. and 2 rnc.
The availability of an isotopically labeled sample of the vitamin K substitute, 2-methyl-l14-naphthoquinone, should make possible a number of biological studies with this substance that hitherto have been impossible. Collins4 has reported an interesting synthesis of this quinone, incorporating carbon-14 into position 8 in the aromatic ring. This report presents a new preparation of the quinone permitting inclusion of carbon-14 in position 4 of the quinoid ring. We have preferred to label in this position because of the report of Shemiakin, et CZZ.,~ of the vitamin K activity of phthalic acid and its diethyl ester and its isolation from the urine of men and dogs after administration of 2methyl-l,4-naphthoquinone.
UCH0
4- (CH,CHzC0)20
over-all yield of 65y0from 2-methylcinnamic acid (I) according to the reaction sequence (I) -+(11) --$ (III) + (IV). Reduction of (E) was carried out successfully a t ice-bath temperature; at higher temperatures, a mixture of the allylic and saturated alcohol was obtained. A purer product (111) was always obtained by isolation of (11) before reduction at 3 atmospheres pressure with hydrogen and platinum or Raney nickel. Since dehydrogenation of (VI) with palladium produced a mixture of phenols and hydrocarbon which could not be readily purified, the ketonic oxygen was removed by the Clemmensen reduction to give (VII). Oxidation of (VIII) to (IX) by a modification of Fieser's method6 was
0' ,
CH=&-CH,OH
CH=&--COOH LiAlH;
-+ 62 %
83 %
I
I1
ptI:Ni;
I
0 I1
I\AJ
'", VI
VI1 crude
VI11
IX
64% based on (VI)
2-Benzylpropyl bromide (IV) was prepared in an (1) Presented before the Division of Biochemistry a t the 116th Meeting of the American Chemical Society, Atlantic City, N. J., September, 1949. (2) (a) This paper is based in part on a thesis submitted by Liang Li to the Graduate School of St. Louis University in partial fulfillment of the requirements for the dexree of Doctor of Philosophy in Biochemistry, November, 1949. (b) Fellow, American Bureau of Medical Aid to China, 1947. (3) Author to whom inquiries regarding this work should be sent. (4) C. J. Collins, THISJOURNAL, 78, 1038 (1951). (5) M. M. Shemiakin, L. A. Schukina and J. B. Shvezov, N o t u ~ e , 161, 585 (1943); 164, 513 (1944).
not as satisfactory as a modification of the method of Hyman and Peter,' the yields being 3741% and 48-52%, respectively. This over-all procedure has been used with no appreciable variation in results with 5 mM. of barium ~ a r b 0 n a t e - C ' ~ of activities of 1 pc., 100 pc. and 2 mc., the overall yield being 25% based on the carbon dioxide used. Biological studies will be reported elsewhere. (6) L. F. Fieser, J . B i d . Chcm., 188, 391 (1940). (7) J. Hyman and C. F. Peter, U. S. Patent 2,402,226 (June 1946).
3-Methyltetralone-l-C14 (VI).-The 818 mg. of (V) was stirred a t ice-bath temperature and 5 . 5 nil. of I-12S04(sp. 2-Methylcinnamic Acid (I).-This material was prepared gr. 1.84) was added dropwise from a buret during the course in 62% yield from benzaldehyde and propionic anhydride by of 40 minutes. After standing 24 hours a t room temperaa modified Perkin r e a ~ t i o n m.p. , ~ 82'.lO ture, it was poured onto crushed ice and the oily product 2-Methylcinnamyl Alcohol (II).-A solution of 24.3 g. of taken up in ether. After washing the ether extract with (I)in 300 ml. of absolute ether was added dropwise with con- water, 5% NaHC03 and water, the ether was removed leavtinuous qtirring during the coiirse of two hours to a solution ing 625 mg. ( 8 5 % ) of a slightly yellow oil. An oxime was of 5.8 g. of I,iAIH, i n 300 ml. of absolute ether tnaintained prepared from 37 mg. of this product and found t o melt a t at 0-5'. After stirring 24 hours, the temperature was per123e . 16 mitted t o rise to 20" during the course of an hour. The 2-Methylnaphthalene-4-C14 (VIII).-The tetralone (588 solution wa.s then cooled below $5' iiig.) was reduced by Cleminenseri reduction using ziiic nil. of water and :iOD l i l l . d IO?;: I 1 ;iiii;iIg;irn,t i nil. of :H70 IICI, O.,'I in1. of glacial acetic mid cthcr laycr successively wit 11 I\-; :-1iiiI (i 1111. of toluciic ill the usual nianner for ii period of 26 water, there was obtained from the dried ethe 1iim-s. Proin the reaction mixture, 456 nig. of a goldeii of (II), b.p. 96-97" at 1.3 mm.,re yclloir oil was obtained which was immediately dehydroThree grains of unchanged acid was recovered. Crystalligenated according t o the procedure of Linstead.16 The oil tion of the alcohol from cold petroleum ether yielded w ~ i sheated at 250" for 3 hours over a palladium-chiircoal olorless, elongated plates, melting at 74.5'. catalyst i i i an 18 X 160 mtn. Pyrex tube fitted with it11 air A n d . Calcd. for CloHzeO: C , 81.04; H, 8.16; quantita- condeiiser. After extraction of the catalyst with ether and tive microhydrogenation, 1 mole of H n . Found: C, 81.70; retno\-al of the ether, 420 mg. of solid was obtained, blicrosubliniation of this product produced 330 mg. of colorless 13, Y.19; quantitative microhydroger~ation, I .OG moles o f crystals ( I U . ~ .34.5') of (VIII) in a yield of 64% based oil 112. A 3,5-dinitrobenzoate was prepared from 50 mg. of (11) the tetralone. This product did not depress the melting which crystallized from petroleum ether (30-60') as color- point of authentic 2-methylnaphthalene. The picrate of a sample of non-radioactive 2-methylnaphthalene also less leaflets, m.p. 125.5-12fi". prepared by this procedure, m.p. 1 1 6 O , did not depress the A n d . Calcd. for C17H140eN2: C, 59.65; H, 4.12. melting point of an authentic sample upon admixture. Found: C, 59.48; H, 3.78. 2-Methyl-1 ,4-naphthoquinone-4-C14 (=).-In a 50-ml. flask provided with a small magnetic stirrer and reflux con2-Benzylpropanol-1 (III).-Ten grams of (11) was rewas dissolved in 0.8 ml. of denser, 1.65 g. of Na2Crz07.2H~0 duced in the usual manner with Raney nickel or platinum and water. To this wts added the 330 mg. of (VI111 dissolved hydrogen to give ( I I I ) , b.p. 77.5-78" :it 0.5 mm. or 1 3 in 5.5 g. of CClr. The contents of the flask were stirred :rt 126.ti" at 1.5 m m . l l 50-55' while 1.7 ml. of 80% HISO, was added tlropuise. 2-Benzvlpropvl Bromide iIV).-PhosDhorus tribrornide The temperature of the bath was gradually raised to 80' i i i (19 g . ) \Cas sid\viy adtied dropaise t o io g. of (1111 \vitIi the coursc of 10 minutrc, held there for 5 minute.;, and then stirring ;it 0'. The reaction mixture was allowed to staiid 18 hours in an ice-bath until the temperature gradually rose the flask was chilled with ice-water. The CC14 layer was removed and the aqueous layer W:IS to room teinperaturc. I t was then heated t o 90-100° for 2--3 hours, cooled, arid poured onto crushed ice. The ether extracted with CCI, and ether; the combined CC14-ether extract was washed with water and dried over anhydrous layer was extracted several times with 5-ml. portions of a freshly prepared alkaline hydrosulfite solution (2% sodium calcium chloride. After removal of the ether, 11 g. of (IV), b.p. 77..5--78" a t 0.5 iniii., was obtained in a yield of hydrosulfite in 2% S a O H ) until no color remained iu the extract. The unoxygenated fraction remaining in the 78%.'2 3-Benzylbutyric-1-0' Acid (V).-The apparatus used for CCld was reoxidized with 1 g. of NasCrZOr2HgO in 0.5 ml. of preparation of this material was similar to that suggested water and 1.0 ml. of 80% HZSO,. The hydroquinone from by Calvin.13 The Grignard reagent was prepared in an both oxidations (225 mg.) was oxidized with 450 mg. of atmosphere of nitrogen in the usual manner from 1.5 g. of Ag20 in the presence of a small amount of anhydrous hIgS04. The crude quinone, 212 mg., m.p. 9&100", was (7.5 mM.) of (IV) and 182 mg. of acid-irrtshed niagnesium turnings. The CO;! for carbonation was obtained from 987 sublimed in vacuo t o give 185 mg. melting at 104.5-105" mg. of barium carbonate-Ci4 coiitaining 09 ~ cof. carbon-llt4 which did not depress the melting point of authentic nonr:tdioactive 2-inethyl-1,4-naphthoquinone. Recrystallizaby acidification with 50 ml. of 80% HzS04arid was flushed through a U-shaped column of anhydrous c;ilciuin chloritle tioii from 50% methanol raised the melting point t o 106.5". Using this method of oxidation of The yield was Sn%. and Drierite into the gas inanifold where ii was distilled JTpnian and Peter,' the over-:tll yield of ( I X ) based on the twice from traps cooled with liquid nitrogen. The flask containing I he Grigiiartl reagent w t s :ttt;ichetl t o the gas C140r u w l w a s 25%. Adaptation of Fieser's method6 manifold, cooled with liquid nitrogen, the nitrogen ;it nios- o f itsit1:ttion o f t h e hvrlroc:irbnii consistently gave yicltls of only .?7--4l%. pherc in the flask removed, and evacuated to a pressure of Radioactivity Assay.-A sample of the product was oxi5 I.(. The Cot.was slowly distilled into the Crignard reagent dized by means of a modified \'an Slyke-Folch wet oxidation over a period of not less than 30 minutes, the liquid nitrogen procedure.l7 was replaced with an ice-salt-bath a t - 15' and the reaction mixture was stirred with a magnetic stirrer for 30 minutes Annl. 6.739 mg. o f _ ( I X ) gave 80.49 mg. of BaCOa. and then brought t o atmospheric pressure with nitrogen gas. Calccl. for CIIH~O,:C, (6.73. Found: C , 76.78. After ten hours, the reaction mixture was hydrolyzed with The radioactivity of this sample of BaC140a was comdilute HCI, the ether layer removed, : t i i d extracted with 10% pared with that of a Bureau of Standards Carbon-14 StandSaOH. The alkaline extrart was aciclifietl , extracted with ard using a thin window Geiger tube (window thickness, 1.7 ether and dried over anhydrous MgSO,. After evaporai ion mg./cm.?i. .Innl. 19.1 microcuries of carbon 14 per milliof the ether, 818 mg. of colorless oil was obtained (91.5%). A non-radioactive preparation w i q distilled a: 127" a t 0.1 inolr nr i n ) . rum. I x v e n c and rqmrtctl b . p 160 :It I nim. Acknowledgment.-The authors are grateful for
Experimental8
__ .
the fruitful discussion, helpful consultation and constant encouragement given by Professor E. throughout the course of this work. We also wish to thank Dr. Thayer for the elemental analyses reported here.
( 8 ) All melting points taken on the Pisher-Johns apparatiis. A. (9) J. R. Johnson, "Organic Reactions." Yol, I. John W'iley and Sons, Inc., New York, N.Y.. 1942, p. 251. noisy (10) P. Raikow, Bet., 30, 3 3 9 i (1887), reported m p. 81-82'. S. A. ( 1 1 ) J. V. Braun. A. Grabowski and G . Kirschbaum. i b i d . , 46, 1278 (19131, reported b.p. 128-126' a t 1B mni. (12) P. A. Leveneand R . E . Marker, .I. Bioi. Chcm.. 110, 303 (19351, Sr. Lours, MISSOURI reported b.p. 85' a t 1 mru 115) W. >,: Bachmann and W. S. Struve, THISJ o u ~ v .
