Noveinber 1966
~~LUOHINATEI) PYIlIiUIDlXES AND
TRIAZIKES
877
SCHEMEI
merit of the yield when ail excebs of hydrogen fluoride w a b used during fluorination. Uracil-5-carboxylic acid (1) was recovered unchanged when treated with sulfur tetrafluoride at room temperature and at SO”, with or without hydrofluoric acid. At 100” in the preqence of hydrofluoric acid, a 77% yield of >-trifluoromethyluracll(2) was obtained.
Hg C1, __c
I
H
H 1
I
2
CHaAO
,j-I:ormyluracil (3a), the precursor of 5-difluoroinethyluracil (4a), was prepared by the ReimerTiemann reaction on uracil as reported by Wiley and T a m a m ~ t o . ’ ~The substitution of the carbonyl by a difluoro function was achieved with sulfur tetrafluoride; the product 4a proved to be labile in alkaline media. In neutral media slow decomposition of 5-difluoromethyluracil to the aldehyde 3a was noted. l5 5-(1,l-Difluoroethyl)uracil (4b) was prepared from 3-acetyluracil16 (3b) by the Tame method to study the inductive effect of the methyl group on the stabilization of the two a-fluorine atoms. Rapid hydrolysis prevented reliable elemental analysis. The ultraviolet spectrum (hydrochloric acid) and the nmr spectrum
9
toluyl
I
+ O
0-tPolu y I 1
10
NaOCH
T V I
toluyl
0-toluyl 11
I
I
H
H 3a, R.=CH=O
4 a , R’=CHF,
b, Fl=COCH,
b, R’=CF2CH,
(trifluoroacetic acid) showed a A,, at 272 mM arid :L triplet due to coupling with the two a fluorines at 1.0 ppm ( J = 20 cps). After several minutes a shift was observed in both spectra that was identical wit,h the $pectra of t,he starting mat.eria1, 5-acetyluracil (3b). OH OH of 5-monofluoromethyluracil was un12a, dextrorotatory mpted by treatment, of the alcohol 7a, [a]D -t76” b. levorotatory b, @ID - 36” with sulfur fluoride-hydrogen fluoride, displacement of the tosylate with potassium fluoride, and halogen exubing chloroacetic acid. Conversion of the carboxyl change using either 5-chloromethyl- or 5-bromomethylat Cg to the trifluoromethyl group was successful at uraril” with silver fluoride or antimony trifluoride. In 50°, giving .i-trifluoromethyl-Ci-asauracil(6), the light of the instability of 5-chloromethyl- and 5bromomethyluracil, l7 difficulty in isolating 5-fluoromethyluracil would be expected. of 5-carboxy-6-azauracil (5) was acrocedure of Barlow and Welch;’* the hydrolysis at Cz was performed in a one-step reaction I H
(14) R. H. Wiley a n d T.Yamamoto, J . O r g . Chem., 25, 1906 (1960). (15) Heidellierger a n d co-lvorkers noted in a pri\-ate communication t h a t a sample of .5-diflnorornethyluracil submitted f o r testing was shown t o be completely converted to t h e corresponding aldehyde in 2 min at pH 6.5 in 0.1 :M phosphate h u f f e r ; a t pH 4.0 i n distilled mater, 507” was converted t o t h e aldehyde in 1;20 min with a s h i f t in p H t o 4 . 3 ; a t pH 1 in HCI, t h e compound was unchanged in 3 hr. (16) L. Clrtisen, Ann., 297, 1 (1887); LV. Bergmann a n d T. B. Johnson, ,
11. G. &I.Srhelatrate, and B. R . Baker, J . Org. Chrm.,
26, 149 (1960); .I. 11. 13iivkJialter, It. .I. driival
