Aug.

20, 1057 COMMUNICATIONS TO THE EDITOR 4559

When deacetylation was allowed to occur a t the latter reaction led us to attempt the preparation of
same p H but a t 5.0 =k 0.2' and the spectrum was 2-fluoroadenosine from 2,6-diaminopurine riboside
scanned from 270-230 mp both before and, a t a by diazotization in fluoboric acid.
series of times, after the addition of base, the re- An aqueous solution of sodium nitrite (360 mg.
sulting difference spectra (inset to Fig. 2) show the in 2.4 ml.) was added with stirring to a solution of
rapid appearance of a peak with its maximum a t 245 2,6-diaminopurine riboside6 (846 mg.) in 48% fluo-
mp which slowly declines with time, corresponding boric acid (9.6 ml.) a t -10'. The solution was
closely to that described for acetyl-imida~ole.~stirred a t -10" to 0" for 15 minutes, cooled to
According to the published extinction coefficient of -20" and neutralized with 50y0sodium hydroxide
this compound4 ( E = 3 x lo3),the observed max- solution. The water was removed in vacuo and the
imum increase and subsequent decrease a t 245 mp residue chromatographed on a Celite column using
is equivalent to 0.41-0.42 mole acetylimidazole per water-saturated butanol. The crude 2-fluoroadeno-
mole of reactive acetyl in the enzyme. Similar re- sine obtained (149 mg.) was recrystallized from ab-
sults were obtained in glycine buffer, but in phos- solute ethanol and dried in vacuo over P z Oa~t 70"
phate the magnitude of the change a t 245 mp was for several hours: yield, 75 mg. (8.7%), dec. a t
reduced. 200'; ( C Y ) ~ ~-60.3
D f 11.1 (0.127y0 in ethanol);
I t is postulated, therefore, that as indicated in h&:x' 260.5 mp ( U M 13,700); A'&,: 260.5 mp ( U M
Fig. 1, the deacetylation of mono-acetyl-d-chymo- 14,300); Xg:x13 260.5 ( U M 14,800). Anal. Calcd.
trypsin occurs by a rapid intramolecular transfer for Cl~H12FNS04. 1/4C2H50H: C, 42.45; H, 4.60;
of acetyl- from serine hydroxyl to imidazolyl- fol- N, 23.60. Found: C, 42.34; H, 4.93; N, 23.40.
lowed by a slower hydrolysis of acetyl-imidazolyl-. A qualitative test for fluorine was positive. The
The first order rate constant for the disappearance ratio of the Rfvalues of 2-fluoroadenosine and ade-
of the E246 compound corresponds closely with that nine in butanol-water on a descending paper chro-
observed for the rate of deacetylation of d-chymo- matogram (Watman No. 1) was 0.9.
trypsin as measured by the reappearance of enzyme 2-Fluoropurine was prepared in the same manner
activity,6 which in turn corresponds t o the rate of from 2-aminopurinee (850 mg.): yield, 254 mg.
base catalyzed hydrolysis of acetyl-imidazole in a
model system.8 (41%) dec. a t 216"; Xgtxl 264 mu ( a 8,300) ~
(8) M. L. Bender and B. W. Turnquest, THIS JOURNAL, 79, 1656 266.5 mp ( U M 8,400), X L:
x 13 272 mp (UM
(1957). 8,800). Anal. Calcd. for C6H3FN4: C, 43.48; H,
DEPARTMENT OF BIOCHEMISTRY GORDON H. DIXON 2.20; N, 40.60. Found: C, 43.52; H, 2.01; N,
UNIVERSITY OF WASHINGTON HANSNEURATH 40.37. A qualitative test for fluorine was positive.
SEATTLE 5, WASHISGTON
I n preliminary tests 2-fluoroadenosine inhibits
RECEIVED JUNE6, 1957 the growth of Human Epidermoid Carcinoma
(HE 2) a t g./ml. Five times this concentra-
SYNTHESIS OF POTENTIAL ANTICANCER AGENTS. tion is required t o inhibit monkey kidney cells.
X. 2-FLUOROADENOSINE' Azaserine and 6-diazo-5-oxo-~-norleucine inhibit
Sir : the growth of these tissues a t lo-' g./ml.
Recently the biological activity of three fluoro The preparation of other 2-fluoropurines is now
derivatives of naturally occurring pyrimidines has under way in this laboratory.
been reported.2
Of these three fluoropyrimidines, 5-fluorouracil (5) J. Davoll and B. A. Lowy, THISJOURNAL, 73, 1650 (1951).
(6) A. Albert and D. J. Brown, J . Chcm. Soc., 2060 (1954).
and 5-fluoroorotic acid have shown appreciable (7) Affiliated with Sloan-Kettering Institute.
tumor-inhibitory activity against a variety of rat
and mouse tumorszaand 5-fluorouracil was selected KETTERING-MEYER LABORATORY'
for clinical trials.2b The biological activity of the BIRMINGHAM SOUTHERN RESEARCH INSTITUTE JOHNA. MONTGOMERY
5, ALABAMA KATHLEEN HEWSON
fluoropyrimidines increased our interest in the prep-
aration of fluoropurines and their ribosides, es-
pecially fluoro derivatives of naturally occurring THE SYNTHESIS OF 5-FLUOROPYRIMIDINES
purines. Although Bendich, Giner-Sorolla and Fox
were unable t o prepare 6-fluoropurine from adenine Sir :
by the Schiemann reaction, Weisbach success- We wish to report the synthesis of a new class of
fully prepared 2-fluoropyrimidine from 2-amino- compounds, some of which were designed to func-
pyrimidine by this method.4 The success of the tion as nucleic acid antagonists, by substituting
( 1 ) This work was supported by funds from the C. F. Kettering fluorine for hydrogen in naturally occurring pyrimi-
Foundation. Part IX, John A. Montgomery and Carroll Temple, J r . , dines.
THISJOURNAL, in press.
(2) (a) C. Heidelberger, D. Morren, L. Griesbach, B. J. Montag, The 5-fluoropyrimidines (111) were obtained
R . Duschinsky, E. Pleven and R. Schnitzer, Proc. A m . A s s . Cancer from pseudourea and pseudothiourea salts (I) and
Research, 8 , 212 (1957); (b) F. A. McIver, A. R. Curreri, 0. 0. Meyer, a-fluoro-@-ketoester enolates (11) by adaptation
R. F. Schilling and H. Waisman, ibid., 9 , 230 (1957); (c) C. Heidel- of the Wheeler synthesis.
berger, L. Bosch, N. K . Chaudhuri and P. B. Danneberg, Federation
Proc., 16, 194 (1957); (d) J. M. Scheiner, E. Kostelak and R. Dus- Crystalline I I a was prepared by the addition a t
chinsky, ibid., 16, 242 (1957); (e) T. Wong and W. M. Benson. ibid., 0
' of 2.4 moles of methyl formate and 1.2 moles of
16, 348 (1957). ethyl fluoroacetate (IV) t o 1.2 moles of potassium
(3) A. Bendich, A. Giner-Sorolla and J. J. Fox, "The Chemistry and ethoxide in 800 ml. of toluene and letting the mix-
Biology of Purines" (A Ciba Foundation Symposium), J. and A.
Churchill Ltd., London, England, 1957, p. 7. (1) H. L. Wheeler and H. F. Merriam, A m . Chcm. J . , 99, 478
(4) D. E. Weisbach, M. S. Thesis, University of North Carolina, (1903); A. Dornow, F. Boberg and L. Schiirer, Arch. Pharm., 886, 494
1954. (1953).
 4660 COMMUNICATIONS
TO THE EDITOR 1.01. 79

hydrolysis of IIIg afforded 52% of 5-fluorocytosine

(IIIh), m.p. 295-297" dec max 985 m p ( E .)
i

8900) (Calcd. for C4H4FN30: C, 37.21; 13,

3.12; F, 14.72. Found: C, 36.92; H, 3.07; F,
+F 14.4'7).
Diethyl oxalate (2 moles), potassium ethoxide
1
R/ "\Ru
1 and IV gave IIc8 (Calcd. for C8HI0FKO5:C, 39.34;
H , 4.12; K,16.01; F, 7.78. Found: C, 39.03;
111 H, 4.34; K,16.48; F, 7.59). Condensation (as de-
I a b c I1 a 11 c d scribed for TIa) of I a and IIc yielded, after process-
R = SEt OMe ShIe R = IC Sa I; H ing IIIi (23y0 from IV), m.p. 168-169' dec. (Calcd.
X = Rr C1 '/,SO4 R' = H II C0,Et CH2F for C9HllFN203S:C, 43.89; H, 4.50. Found:
I11 a b c d e f g h 1 j 1-
_- 1 C, 43.96; H , 4.61). Hydrochloric acid
R = SEt OH OMe SMe SH SEt SEt OH SEt OH Shfe OH hydrolysis of IIIi yielded 88% of 5-
R' = OH OH OH OH OH C1 NH2 NH, OH OH OH OH fluoroorotic acid monohydrate (IrIj)
R" = H H H H H H H H COZEt COZH CH2F CHICI m,p. 2550 dec., h;O.:HCl 234-233 mp
ture stand a t 25' for 16 hours.2 After ITa was ( E 7100)3 (Calcd. for C6H3FN~O4,H2O: C, 31.2G;
refluxed for 2 hours with 0.6moles of I a and 0.6 H , 3.13; F, 9.89. Found: C, 31.36; H, 2.93;
moles of sodium methoxide in 1440 ml. of ethanol, F, l O . l l ) , which on refluxing in Dowtherm yielded
evaporation, extraction with water and acidifica- 86% of IIIb.9 Condensation of IC and IId'" (2
tion gave I I I a (24y0 yield from IV), m.p. 192- moles sodium methoxide) gave I I I k m.p. 221-222"
193' dec. (recrystallized from ethyl acetate) dec. which was impure, due to partial loss of side
(Calcd. for C6H,FN?OS: C, 41.38; H , 4.05; F, chain fluorine (Calcd. for C6H6F?N20S: C ,
10.91. Found: C, 41.45; H, 4.25; F, 11.48.) 37.49; H, 3.15; F, 19.77. Found C, 37.08; IT,
Hydrochloric acid hydrolysis' of IIIa afforded 727, 2.79; F, 13.01). This upon refluxing with hydro-
of 5-fluorouracil (IIIb), m.p. 282-283' dec., chloric acid yielded I11 (40y0 over-all yield from
~ 0 . 1 " HCl 96-
max 2-266 mp (E 7070)3 (Calcd. for C4- IId) m.p. 240-241" dec. (Calcd. for CbHPClFX20?:
I

H3FN202: C, 36.93; H, 2.32; F,14.61. Found: C, 33.63; H, 2.26; C1, 19.86; F, 10.04. Found:
C, 37.07; H, 2.30; F,14.69). Similarly I b and I I a 34.03; H, 2.11; C1, 19.47; F, 10.64).
gave IIIc, m.p. 206-207' dec. (Calcd. for C6H6- 5-Fluorouracil and 5-fluoroorotic acid have pro-
FN2Op: C, 41.67; H, 3.50; OCH3, 21.63; F, 13.18. found activity" against bacteria in vitro and against
Found: C, 42.01; H,3.87; OCH3,21.70; F, 13.51). several transplanted tumors in animals. The for-
This was hydrolyzed to yield IIIb. Hydrogenation mer is under clinical investigation in neoplastic
of I I I b (1 mole hydrogen) with palladium charcoal diseases.
in 2 moles of sodium hydroxide yielded 80% of ura- We are indebted to Mrs. Ellen Chiandera for
cil, whereas rhodium catalyst4 in acetic acid pro- technical assistance and to Dr. A1 Steyermark for
duced a mixture from which 6.576 of 5-fluorodi- the microanalyses.
hydrouracil, m.p. 237-238' dec. (Calcd. for Cq- (8) C j . I. Blank, J. Mager a n d E. D. Bergmann. J . r h e i n . S O L ,
H5FN202:C, 36.37; H, 3.82; F,14.38. Found: 2192 (1955).
(9) This method produced 2.C1'Iabeled I I I b from l a via IIIj.
C,36.32; H, 3.43; F,14.59) was isolated by cel- (10) E. T. McBee, 0 . R. Pierce, H. W.Kilbourne and E. R. Wilson,
lulose powder chr~matography.~Condensation THISJ O U R N A L , 75, 3152 (1953).
of IC and IIa gave IIId, m.p. 241-243' dec. (Calcd. (11) C. Heidelberger, N. K . Chaudhuri, P. Danneberg, D . Mooren,
for C5H~FNzOS:C, 37.49; H , 3.15; N, 17.49. L. Griesbach, R. Duschinsky, R. J. Schnitzer, E. Pleven and J. Scheiner,
Found: C, 37.98; H, 3.44; S , 17.52) which on de- Nature, 119, 663 (1957).
methylation6 afforded 49% of IIIe, m.p. 227-229' RESEARCH LABORATORY ROBERT DUSCHINSKY
dec. (Calcd. for C ~ H Z F N ~ OC, S : 32.87; H , 2.07; HOFFMASN-LA
NUTLEY,
R O C H E IXC.
NEWJERSEY
EDYARD PLEVBN
F, 13.00; Found: C, 33.45; H , 2.36; F, 12.78). M C A R D L E MEMORIAL LABORATORY
Chlorination' of I I I a produced oily IIIf, which by THEMEDICALSCHOOL, USIVERSITYOF WISCOSSIS
autoclaving (12 hours, 100') with liquid ammonia R~ADISOS, ~VISCONSIN CHARLES HEIDELHERGER
gave IIIg, m.p. 94', in 88% over-all yield (Calcd. RECEIVED JULY 1, 19.57

for CeHsFSN3:C,41.60;H , 4.66; N, 24.26. Found:

C , 41.43; H, 4.73; N, 23.96). Hydrobromic acid SOME SELECTIVE REACTIONS OF THE SILICON-
(2) T h e compound is impure a n d unstable; i t should be used without
u n d u e delay in the next step. In a similar run with sodium ethoxide
t h e obtained I I b was converted b y t r e a t m e n t with ethanolic hydro-
chloric acid a t 25' i n t o ethyl fluoromalonaldehydate diethyl acetal
(9.3% f r o m 11'). b.p. 115-118" (24 m m . ) , nZ8D 1.4011. (Calcd. f o r
C ~ H I I F O I :C , 51.81; H, 8.23; F, 9.12; OCzHs, 04.92. Found: C ,
52.19; H, 8.38; F , 9 . 0 2 ; OC*Hs,64.55.)
(3) D a t a supplied b y Dr. A. Motchane.
(4) W. E. Cohn a n d D. G. Doherty, T H I S J O U R N A L , 1 8 , 2863 (1956).
(5) T h e upper phase of a mixture of ethyl acetate, water, formic
acid (60:35:5) was used a s eluant. Cf. K. Fink, R. E. Cline, R. B.
Henderson and R. M. Fink, J. B i d . Chem., 221, 430 (1956). T h e
collaboration of Mr. W. E. Oberhansli in t h e chromatographic work
is gratefully acknowledged.
(6) H. W. B a r r e t t , I. Goodman a n d K. D i t t m e r , THISJ O I J R N A T . ,
T O , 1755 (1948).
( 7 1 f 1 I,. \$'heeler a n d T R.J o h n w n , A m . Chenz. J . , 29, 4!Xi I IY03).
HYDROGEN GROUP WITH ORGANOMETALLIC
COMPOUNDS
Sir :
We are reporting a series of reactions which
readily make available the synthesis of a wide
variety of organosilicon compounds, particularly
those of an unsymmetrical nature. The intro-
duction of the various R groups can be effected
stepwise by the proper choice of solvent and organo-
metallic compound. The synthesis is particularly
appropriate for the preparation of low-melting
organosilicon compounds of the type R4Si where all
of the R groups can be different.
Previoiir r e p o r t 5 have 4iiow11 th,rt o r j y i i o l i t l i -