[CONTRIBUTION FROM
THE 1)EPARTMENT OF
CHEMISTRY, OREGON STATE COLLEGE]
Purines. I. The Chlorination of Certain Purinones with Phosphorous Oxychloride in the Presence of Aliphatic Tertiary Amines1 BY ROLANDK. KoRixs
AND
BERTE. CHRISTEXSEN
RECEIVED DECEMBER 21, 1951 The reaction of uric acid, xanthine and hypoxanthiiie with phosphorus oxychloride in the presence of various aliphatic tertiary amines has been shown to result in the replacement of the “hydroxy” group in the 6- and in some cases the 2- and 6positions of the purine nucleus to give the corresponding dialkyl- or bis-(dialky1)- aminopurine in good yield. The structures of a number of the dialkylaminopurines have been established by syntheses. 8-Chloroxanthine has been prepared in good yield from the monopotassium salt of uric acid bv the action of phosphorus oxychloride and a limited amount of triethylamine. An excess of triethylamine in the same reaction has been found to yield 3,8-dichloro-6-diethylaminopurine.
Since Baddiley and Topham? first chlorinated In order to determine the position of this substitbarbituric acid in the presence of dimethylaniline, uent, trichloropurine was treated with diethylthe use of this tertiary amine and phosphorus amine; this gave a product which was found to be oxychloride has found extensive application in the identical to (I, R = C2H6). The reaction 6f a preparation of numerous chloropyrimidines. I t secondary amine with trichloropurine has not been would seem logical that this reaction may well be previously described, but 2,6-dichloro-7-methyIexpanded to the preparation of the rather rare chloro- purine’ has been reported to yield 2-chloro-6purines, which could serve as valuable intermedi- diethylamino-7-methylpurine. Thus it would inates in the preparation of synthetic n~cleosides.~dicate that the 6-position may be the more reFor this reason a study of the behavior of di- active one in trichloropurine. This opinion was methylaniline in a reaction mixture of phosphorus confirmed, and the structure of (I) provenwhen oxychloride and several purinones was undertaken. the reduction product of (I) with hydriodic acid Preliminary experiments with uric acid were was found to be 6-diethylaminopurine (11) which not promising; short periods of reaction time was identical to the reaction product of hypoxancommonly employed in the preparation of chloro- thine, triethylamine and phosphorus oxychloride. pyrimidines were found to have little effect in Xanthine with phosphorus oxychloride and trichlorinating the purine ring. Longer periods of ethylamine gave 2,6-bis-(diethylamino) -purine. reaction time resulted in considerable phosphorylaTo establish the generality of this reaction the tion of the dimeth~laniline~ as well as in the produc- study was expanded to the use of other tertiary tion of a large amount of a phosphorylated, parti- amines in the reaction mixture. Trimethylamine, ally chlorinated derivative of uric acid and in isola- xanthine and phosphorus oxychloride yielded a tion of very little of the desired trichloropurine. product 2,G-bis-(dimethylamino)-purine(111, R = Recently, Davoll and Lowy5 reported an isolation CH,). I t is interesting to note that these reactions of 16-2570 yield of trichloropurine from uric acid can be operated a t atmospheric pressures ; this using dimethylaniline and phosphorus oxychloride. would suggest some type of salt formation in the I n view of these results several routine chlorina- reaction mixture. When tri-n-propylamine was tions using other tertiary amines were attempted. used, the reaction product was not the expected In the course of this work i t was discovered that in 2,6-di-n-propylamino derivative but a compound the presence of a limited amount of triethylamine having the empirical formula CllH17N50 (IV, R = uric acid was converted to 8-chloroxanthine in C3Hi) ; with tri-n-butylamine, C13H2iN60 (IV, R = yields of from 3 0 4 0 % ; by the substitution of mono- (I4H9)was obtained. I t thus appears that only potassium salt of uric acid the yields were consist- one of the “hydroxy” groups in xanthine had been ently above 8Oc;h. These results were interesting replaced by the dialkylamino radical in each case. since in the usual chlorination procedure it is the In order to‘prove this and to establish the position of the dialkylamino group, the unambiguous %position which is the last to be chlorinated.6 was unWhen these experiments were extended to the synthesis of 6-di-n-butylamino-2-purinone use of excess triethylamine coupled with longer dertaken. Using trichloropurine and di-n-butylamine, 2,8reaction time, i t was discovered that the reaction riot only chlorinated the purine ring but the tri- dichloro-6-di-n-butylaminopurine(I, R = C4H9) ethylamine proceeded to ammonate the ring. Uric was prepared by a similar procedure to that preacid under these conditions gave a product CgHii- viously employed to synthesize (I, R = C B H ~ ) ClnN6(I, K = C&) instead of the expected tri- hy the second method. I (R = C4H9) was then chloropurine ; this indicated that the product treated with sodium ethoxide which gave 8-chlorocontained a diethylamino-substituent. 3-ethoxy-G-di-n-butylaminopurine(V) by a procedure similar to that employed by Fischer6 to (1) This work was supported in part by grants from the Division of Research G r a n t s a n d Fellowships, National Institutes of Health, Public prepare 8-chloro-2-ethoxy-6-aminopurine from 2,8Health Service. Published with the approval of t h e Monographs dichloro-6-aminopurine. (V) in turn was treated Publications Committee, Oregon State College, a s Research P a p e r No. with hydrogen iodide which cleaved the ethoxy I H i , School of Science, Department of Chemistry. (2) J. Baddiley and -4.Topham. J . Chem. Soc., ti78 f l 9 4 4 ! . group and removed the chlorine atom to give 6-di( 3 ) J . Davoll, 13. 1,ythgoe a n d A. R. Todd, i b i d . . 833 (1940). .1r-hutylamino-2-1,urinone (IV). This compound 14) R Robirisand U E. Cliristenseii, .I. Orq C h i n , 16, 324 ( l % l J . (a) J . Davoll and R .
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