Sept. 20, 1082
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5’ gave p-blromo-a-trifluoromethylpropionamide (11) in 73% yield, m.p. 101-103’. (Anal. Calcd. for C4H5NOFaBr:C, 21.54; H , 2.29; N, 6.36; F, 25.91. Found: C, 21.99; H, 2.39; N, 6.52; F, 25.77.) Condensation of this bromoamide with a 2 to 4 molar excess of urea in aqueous dioxane a t 90’ gave the monosubstituted urea (111) in ca. 30% yield, m.p. 169-171’ nal. Calcd. for CbHsN~F302 .C2HsOH: C, 34.29; H , 5.72; N, 17.14; F, 23.24. Found: C, 33.87; H , 5.18; N, 17.27; F, 23.64). On refluxing this compound in 5 N hydrochloric acid, hydrolysis of the amide group first occurred, then cyclization giving the dihydropyrimidine (IV) in 60Yc yield m.p. 203-205’ dec. ( A n d . Calcd. HARRY B. GRAY for C5HjN202F3:C, 33.00; H , 2.77; hi, 15.38; F, DEPARTMENT OF CHEMISTRY RAYMOND ~VILLIAMS 31.30. Found: C, 33.11; H, 2.81; N, 15.20; F, COLUMBIA UNIVERSITY I BERNAL 31.26). Treatment of (IV) in acetic acid under reNEW YORK27, NEW PORK E. BILLIG fl.ux with one mole of bromine gave the bromohydroRECEIVED JULY 31, 1962 pyrimidine (V) in 70yo yield, m.p. 218-221’ dec., which on heating in dimethylformamide13for 1 hour SYNTHESES OF 5-TRIFLUOROMETHYLURACIL AND a t 140’ gave 5-trifluoromethyluracil (VI) in 85% yield, m.p. 239-241’ dec. (-4nal. Calcd. for C6H35-TRIFLUOROMETHYL-2’-DEOXYURIDINE‘ N2F30s: C, 33.35; H , 1.68; N, 15.55; F, 31.65. Sir : Found: C, 33.75; H, 1.02; N, 15.40; F, 31.96), We wish to report the syntheses of 5-trifluoromethyluracil (VI) (“trifluorothymine”) and its de- pk, (water) 7.35, (method of Shugar and Fox”) oxyriboside 5-trifluoromethyl-2’-deoxyuridine(VTI) Ultraviolet absorption spectra, in 0.1 1%7 hydrowhich was done in connection with the inter- chloric acid Xmax 257 mp, E molar 7050; in pH 7.0 est of this laboratory in fluorinated pyrimidines. buffer, Amax 257 mp, E molar 6830; in pH 8.1 buffer Replacement of the hydrogen atom of carbon-5 of Amax 279, E molar 6900; Ri, butanol/water, 86/14 uracil by fluorine gives 5fluorouraci1, which is in- v./v. ascending 0.79; butanol/acetic acid/water, corporated into ribonucleic acid, and inhibits the 50/20/30 v./v., descending 0.80; ethyl acetate/ growth of murine and human tumors as a result of methyl alcohol/water/n-heptane, 10/6/5/3 v./v., the inhibition of thymidylate synthetase4 by 5- upper phase12 0.76. The 5-trifluoromethyluracil was converted quanfluoro-2’-deoxyuridine-5’-monophosphate.5Retitatively to 5-carboxyuracil in 20 minutes a t room placement of the same hydrogen atom by chlorine, bromine, or iodine leads to compoundsfithat are in- temperature in 1.0 N sodium hydroxide, and in 24 corporated into deoxyribonucleic acid in place of hours in 0.1 N sodium bicarbonate. The lability of thymine, presumably because of the similarity in the trifluoromethyl group in alkali may prove to be sizes of these atoms and the methyl group of thy- of some interest for chemical mutagenesis since it mine. We considered, therefore, that similar effects could be converted to a carboxyl group under condimight be produced by the replacement of the methyl tions which would not degrade deoxyribonucleic group of thymine by a trifluoromethyl group, acid. 5-Trifluoromethyl-2 ‘-deoxyuridine (VII) has been which would also have a similar size. Other trifluoromethylpyrimidines have been pre- prepared using a nucleoside phosphorylase preparapared recently by Tnoue, Saggiomo and NodiF and tion13 from Ehrlich ascites cells, and 2 - d e o x y - c ~ ~ by Rarone,8 but the trifluoromethyl group has not ribose-1-phosphate. The deoxyribonucleoside was been introduced into the crucial 3 position of a py- separated from the unconverted 5-trifluoromethyluracil by electrophoresis on paper in borate buffer rimidine. Trifluor~methylacrylonitrile~(I) dissolved in pH 9.2, and purified by paper chromatography usethanol and saturated with hydrogen bromide a t ing a butanol/formic acid/water, 77/10/13 v./v., descending solvent system. It was obtained in an (1) This work was supported in part by a grant iC-2832) from the over-all yield of 8.2Yc m.p. 169-172’. National Cancer Institute, A-ational Institutes of Health, U. S. Public (Anal. Calcd. for C10HllN205F3:C, 40.55; H, Health Service, and a training grant (CRTY-5002) from the Xational Institutes of Health, U. S. Public Health Service. 3.73; F, 19.24. Found: C, 40.50, H , 4.15; F, ( 2 ) C. Heidelberger, i T.K. Chaudhuri, P . Ilanneherg, I). Llooren, 18.95.) Ultraviolet absorption spectra, in 0.01 N L. Griesbach, R . Uuschinsky, R. J. Schnitzer, E. Pleren and J . hydrochloric acid, X,, 280 mp, E molar 9590, in Scheiner, S a t u v e , 179, GG3 (1937). 0.01 N sodium hydroxide, A,, 260 mp, E molar (3) N. K . Chaudhuri, B. J. M o n t a g a n d C. Heidelberger, C a n c r v Res., 18, 318 (1928). 6250; Rf butanol/formic acid/water, 77/10/13 ( 4 ) L. Bosch, E. Harbers and C. Heidelberger, ibid., 18, 305 (19%). v./v., descending 0.72, ethyl acetate/methanol/ ( 5 ) K-U. Hartmann and C . Heidelberger, J . Bid. C h e n . , 236, 3006 waterln-heptane 10/6/5/3 v./v. descending 0.62. (1901).
1000 cm.-l and A, in the range 3000-10,000 cm.-’ then are consistent with the 4A2, around state for R2Co(MNT):, and the lAlg grouid state for RzNi (MNT)9. The eldctronic spectrum of R2Co(MINT)2in the solid or in D M F solution shows a band a t 12,500 (xz,y z cm.-’ ( E = 891, assigned to the 4A2g 4Eg(1) + 9 ) transition. This gives A3 = 9,500 cm.-l. The next band, a shoulder indicative of a maximum a t 15,000 cm.-’ ( E 200)) is assigned 4 A 2 g + 4Eg(2)(xz,yz -+ xy), giving A2 = 5,300 cm.-l, in agreement with the value assumed above for A,. The bands a t higher energies are much more intense and probably are due to charge transfer transitions. ~
(6) F. Wegand, A . Wacker and H. Dellweg, 2 . A’atuufwovrh , 7 6 , 19 (1952). (7) S. Inoue, A. J. Saggiomo a n d E. A. Xodiff, J . Ova. Chewz., 26, 1501 (1961). (8) J. A. Barone. E. Peters and 11. Tieckelmann, ibid., 24, 198 (1959). (9) Rf. W. Buxton, Xf. Stacey a n d J . C. Tatlow, J . Chern. S O L .36C. . (lQ54).
(10) J. E. Gearien and S . B . Binkley, J . Ovg. C h e n . , 23, 1 9 1 (1958); N. W. Gabel and S. B. Binkley, i b i d . , 23, 643 (1958). (11) D. Shugar and J. J. Fox, Biochim. Biophys. Acta, 9, 199 (19.52). (12) J. F. Codington, I. Doerr, D. Van Praag, A . Bendich and J . J. Fox, J . A m Chem. Soc., 88, 5000 (1961). (13) H. Pontis, G. Ilegcrstedt and P. Reichnrd. Biochim. B i o p h y s . Acta, 61, 138 (19Gl).
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