[CUNTRIBUTION FROM
THE L O S
ALAMOSSCIENTIPIC LABORATORY O F THE UNIVERSITY
OF
CALIFORNIA]
Micro-syntheses with Tracer Elements. VII. The Synthesis of 2-Methyl-C1*-1,4naphthoquinone (Provitamin K) BY ARTHURMURRAY I11 AND ANTHONY R. RONZIO RECEIVEDOCTOBER11. 1951
2-Methyl-C1*-l,4-naphthoquinone, possessing a specific activity of 57.4 mg./mc., was synthesized in a n over-all yield of 48.753, based on methyl-Cl4 iodide. The reaction sequence involved treatment of 2-naphthyllithium with methyl-C14 iodide, followed by oxidation of the hydrocarbon so obtained to the quinone. An improved synthesis of methyl-C14 iodide is reported. Conditions for the 85@hinterconversion of 2-iodonaphthalenc and n-butyllithium are given.
A sample of 2-methyl-l,4-naphthoquiiionefied product. Control experiments in which purilabeled with C1*and possessing the highest possible fied 2-methylnaphthoquinone was carried through specific radioactivity was desired for metabolic this oxidation procedure gave a quantitative return studies in conjunction with studies using the CI4- of unchanged quinone. labeled drugs Pelentan and Dicumarol. The Experimental compound has been labeled in the ring with C1* (1) 2-Naphthyllithium.-This material was prepared esby Collins.2 Since the ring labeled compound was sentially by the method of Gilman and Moore6 using the not necessary for our purpose, a much simpler halozen-metal interconversion reaction between 2-iodosynthesis yielding the compound labeled a t the naphuhalene and n-butyllithium ( a t -30°, 10-30 min.) in yields of 8547%. methyl group was devised and is here reported. 1 2 ) Methvl-Ci4 Iodide.-To one end of a thick-walled The introduction of the methyl-C14 group was Pyre; glass lube (20 X 250 m m . ) was sealed a thick-walled thoroughly explored using methyl halides and the glass chamber of 10-ml. capacity and containing a glass enorganometallic reagent obtained by: (1) the halo- closed magnetic stirrer and to the opposite end was sealed a pressure stopcock (4 mm. bore) which was in gen-metal interconversion reaction; ( 2 ) the halogen conventional turn sealed to a semi-ball joint. The tubular portion of the replacement reaction ; (3) the Grignard reaction. apparatus was enclosed with a water jacket for cooling. The latter two reactions were unsatisfactory be- Through a fine-stemmed funnel passing through the bore of the stopcock was added 7 ml. of hydriodic acid (d. 1.7). cause naphthalene was formed as a by-product. The apparatus was then attached t o the vacuum system. The 2-naphthyllithium reacted with niethyl-C1i The acid was frozen with liquid nitrogen and the chamber iodide to give 2-methyl-C'4-naphthalene which evacuated t o 0.01 nun. 1Veighed amounts of methanol was oxidized to the quinone. (8.81-5.10 millimoles) were transferred in vapor phase into A study of the halogen-metal interconversion the reaction chamber which was then closed off from the \Vater was circulated through the cooling jacket reaction showed that the only by-products were aiystrin. n d the contents were stirred while being heated for two 2,,2'-dinaphthyl (m.p. 180-18lo), fz-butyl halide hours a t 80--85O with an oil-bath. Heating periods tried, and a trace of %naphthyl ethyl ether, all easily varying up to six hours, indicated two hours t o be satisfacIIJrJ-. The reaction chamber was cooled t o room temperaremoved, ture and thc methyl iodide was slowly distilled into an evacuThe effect of lowering the temperature of re- ated reservoir cooled with Dry Ice-acetone, through a puriaction was to decrease the formation of the di- fying train of dried soda lime and phosphorus pentoxide. naphthyl. At -60" the reaction was too slow to The transfer was completed by warming the reaction chanibe useful, while a t -26' the yield of product was ber with hot water and cooling the reservoir with liquid tiitrogen, The reservoir was then freed of non-condensible constant when the duration of interconversion was residual gases, while still cooled with liquid nitrogen, and varied from ten minutes to one hour. The solu- warmed t o room temperature and weighed. The yields of tions of 2-naphthyllithium were stable for 24 methyl iodide from three trial runs mere 99.3, 100.3 and 9 6 . 7 ~ o . One sample of the methyl iodide was distilled into hours when stored a t 0'. solution of 1.5 g. of silver nitrate in 100 ml. of alcohol and The coupling of 2-naphthyllithiuni with methyl awaled off. After warming :it 40" for several days, the prebromide and methyl iodide gave 95-100% yields cipitated silver iodide was filtered and weighed. The yield of 2-methylnaphthalene. Since the n-butyl halides of iodide was 100.3% ba.;ed on methyl iodide and 97.070 interfered in the subsequent oxidation of the 11ascti on methanol. The yield of colorless, homogeneous methyl-C14 iodide methylnaphthalene, they were removed by forming from 0.1295 g. (4.04 millimoles, 12 m c . ) of methanol-C"mas the tertiary amine salts with piperidine." o 3i8.5 g (100%) Several methods for the oxidation of the rnethyl13 1 2-Methyl-CI4-naphthalene -Into 100-in1 flask naphthalene to the quinone were tried. The cquipped witli a magnetic stirrer, a connection to the vacs>-itclll, aiid n closed addition tube, and which had method of Lucas and Pressman4 showed the most uum l~eciiflushed out with pure, dry nitrogen, was introduced promise and was modified to adapt it to a micro :i solution of 3.08 g. (12.13 millimoles) of 2-iodonaphthalene scale and for use with a radioactive compound. i i i nil. of ether. The flask w a s cooled to -30" and a soluThe modified procedure: gave SOTo yields of puri- tion of n-hutgllithium (8.08 millimoles) in ether was added (1'1 Work done under t h e auspices of t h e A.B.C. JOURNAL, 73, 1038 (1951). (2) C. J. Collins, THIS (3) J. Semb and S. &I. McElvain, (bid., 53, 690 (1931). ( 4 ) H. J. Lucas and D. Pressman, "Principles and Practice in Organic Chemistry," John W i l e j and Sons, Inc., S e w \;ark, T.Y . , 1049, p. 442, ( 5 ) For complete experimental details of t h i s oxidation order Docnment 3568 from American Dociimentation Iustituie, l i l ! ! X S t r e r t , N. W., Washington 6, D. C.. remitting $1.00 for microfilm (images I inch high on standard 35 mm. motion picture film) or 31 00 for phot
