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3286 Berptann, Coken, and Shahak :
667. Organic Fluorine Compounds. Part XU.* Preparation
and Reactions of Diethyl Fluoromalonate.
D. BERGMANN,
By ERNST SHAHAK.
COHEN,and ISRAEL
SASSON
The exchange reaction of diethyl bromomalonate with potassium fluoride
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gives only diethyl difluoromalonate, but diethyl fluoromalonate has been
prepared by pyrolysis of diethyl oxalofluoroacetate and by reaction of diethyl
sodio-fluoroacetate with ethyl chloroformate. Some reactions of diethyl
fluoromalonate have been investigated.
THEvariety of syntheses possible with diethyl malonate and the biochemical properties
of malonic acid made fluoromalonic acid an attractive compound. LaZerte and his
co-workers have described an %stage synthesis of this acid from trifluorochloroethylene,
but a more convenient route appeared to be by reaction of diethyl bromomalonate with
potassium fluoride a t 180-190°.2 When this reaction was repeated or carried out in
acetamide as solvent: a fairly constant-boiling product was obtained which had the
expected carbon and hydrogen content, but contained only half the expected amount of
the fluorine; it was a mixture of 3 parts of diethyl malonate and 1 part of diethyl difluoro-
malonate. The latter was obtained pure by brominating the mixture and separating
diethyl difluoromalonate by distillation from the bromination products of the malonate.
Also the amides prepared from the mixture could be separated by fractional recrystallisation
from water. Difluoromalondiamide had the melting point indicated in the literature *
for a product obtained by a different route. It seemed possible that the monofluoro-
malonate first formed might undergo the reaction, CHF(CO,Et), CHBr(CO,Et),+
CH,(CO,Et), +CFBr(CO,Et),, the bromofluoro-ester then undergoing further halogen
exchange, but this should lead to a 1 : 1 mixture, so the reaction is clearly more complex.
Diethyl monofluoromalonate was obtained by (a) pyrolysis of diethyl oxalofluoroacetate
at 210-220" (34% yield), analogously to the formation of diethyl methylmalonate from
diethyl oxal~propionate,~ and (b) by reaction of ethyl sodiofluoroacetate, which is fairly
stable,6 with ethyl chloroformate (20-25y0 yield). A higher-boiling fraction C,H,,O,F,,
obtained in the latter reaction, was diethyl a-fluoro-a-fluoroacetylmalonate,
CH,F*CO*CF(CO,Et),. Hydrolysis and ammonolysis were accompanied by " acid
fission " and led to fluoromalonic acid and fluoromalondiamide, respectively. It is
assumed that part of the enol of ethyl fluoroacetate is converted into the enol of ethyl
ay-difluoroacetoacetate and only then reacts with ethyl chloroformate (see preceding
paper).
In an attempt to prepare 5-fluorobarbituric acid (11), diethyl fluoromalonate was
condensed with S-ethylisothiouronium bromide in the presence of sodium methoxide.
U
(1) (11) (1") (IV)
The 2-ethylthio-5-fluoro-4,6-dihydroxypyrimidine (I) obtained gave, with the usual
reagents (aqueous hydrochloric, hydrobromic, or chloroacetic acid) only a water-soluble
* Part XI, preceding paper.
LaZerte, Rausch, Koshar, Park, Pearlson, and Lacher, J . Amer. Chem. SOC.,1956, 78, 5639.
* Gryszkiewicz-Trochimowski, Sporzynski, and Wnuk, Rec. Trav. chim., 1947, 66, 413.
Bergmann and Blank, J., 1953, 3786.
Henne and deWitt, J . Amer. Chem. SOC.,1948, 70, 1548.
Cox and McElvain, Org. Synth., 1943, Coll. Vol. 11, p. 279.
Bergmann and Szinai, J., 1956, 1521; Bergmann, Cohen, and Shahak, preceding paper.
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[19591 Organic Fluorine Compounds. Part X I I . 3287
liquid from which no trace of the barbituric acid could be isolated. Similar behaviour of
5-chlorobarbituric acid towards hydrobromic acid has been reported, though 5-bromo-
barbituric acid is claimed to be stable towards hydrochloric acid.' The barbituric acid
could also not be obtained from fluoroacetylurea and oxalyl bromide, but it was prepared,
in 16% yield, from ethyl fluoromalonate and urea in presence of sodium methoxide.
5-Fluoroalkylbarbituric acids have been described by Bruce and Huber * and by O'Neill
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and P a t t i ~ o n . ~
Condensation of diethyl fluoromalonate with acetamidine gave 5-fluoro-4,6-dihydroxy-
2-methylpyrimidine (111) and with guanidine gave 2-amino-5-fluoro-4,6-dihydroxy-
pyrimidine (IV) .
EXPERIMENTAL
DiethyE DifEuoromalonate.*o-Diethyl bromomalonate (300 g.), acetamide (100 g.) and
potassium fluoride (113 g.) were heated a t 160-170" under reflux with stirring for 1.5 hr.,
then distilled in 'uacuo to dryness. The distillate was washed repeatedly with water (to remove
acetamide), dried (Na,SO,), and fractionated. Two fractions were obtained: (a) 90 g., b. p.
100-105°/23 mm., (b) 20 g., b. p. 110-140"/23 mm., mainly unchanged bromomalonate.
Fraction (a) contained about 5% of fluorine, equiv. to about 16% of diethyl difluoromalonate.
Fraction (a) (60 g.) in carbon tetrachloride (60 ml.) was heated with bromine (62 g.) as in the
preparation of diethyl bromomalonate.ll Distillation of the product yielded diethyl di$uoro-
mazonate (14 g.), b. p. 94-95"/23 mm., vmX (liquid film) 3000s, 1 7 5 0 ~ s1450s,
~ 1310vs, 1220-
1300vs,br, 1063vs, lOlOvs, 840,862s, 780 cm.-l (Found: F, 19.4. C,HloO,F, requires F, 19*470).
DifEuor0maZondiaunide.-Diethyl difluoromalonate (5 g.) was treated with excess of concen-
trated aqueous ammonia, with occasional shaking, and the mixture kept overnight a t 0".
The precipitated difluoromalondiamide (2 g., 57%), when washed with water and recrystallized
from water, had m. p. 205-206" (lit., 206-207" 4, 200-201" g, , ,v (KBr pellet) 3400, 3200,
1695 (all vs), 1620s, 1390s, 1290, 1130s, 1075s, 695 cm.-l (Found: C, 26.5; H, 3.2; N, 20.7.
Calc. for C,H,O,N,F,: C, 26.1; H, 2.9; N, 20.3%). When 20 g. of fraction ( a ) were treated
with an excess of concentrated aqueous ammonia as above, a small amount of difluoromalondi-
amide, m. p. 205-206", was obtained. The combined mother-liquors were evaporated t o
dryness and the residue was recrystallised from ethanol, to yield malonamide (3.5 g.), m. p.
and mixed m. p. 169-171'.
Diethyl FZuoroma2onate.-(a) Diethyl oxalofluoroacetate l2 (31 g.), with a few porcelain chips,
was refluxed a t 210-220" for 12 hr., then fractionated under reduced pressure. DiethyZfEuoro-
malonate (9 g., 34%) had b. p. 121-122"/30 mm., nD27 1.4040 (Found: C , 47-2; H, 6-1; F, 11-2.
C,H,,O4F requires C, 47.2; H, 6-2; F, 10-7%), , ,v (liquid) 3000, 1780, 1750 (all vs), 1474, 1455,
1380s, 1340vs, and 1280vs (C-F), 1170vs, 1070vs, 1090, 1040, 860, 790 cm.-l.
(b) To a suspension of sodium methoxide (8.1 g.) in light petroleum (b. p. 50-70"; 100 ml.),
ethyl fluoroacetate (15.9 g.) was added a t 15-25' in small portions and with vigorous shaking
(not stirring). After further 10 minutes' shaking, the sodio-derivative formed voluminous,
yellow crystals. The mass was cooled a t -10" and ethyl chloroformate (16.3 g.) in light
petroleum (30 ml.) added as quickly as possible, but so that the temperature did not rise above
25". The mixture was shaken for 1 hr. a t room temperature, refluxed for 10 min. and decom-
posed with water (100 ml.) . The organic layer was washed with 1% sodium hydrogen carbonate
solution, dried (MgSO,) , and distilled through a short column, first a t atmospheric pressure, then
under 30 mm. The fraction boiling a t 100-130°/30 mm. was redistilled under atmospheric
pressure (204-205') and had b. p. 121"/30 mm. (5-5-6.5 g., 20-25%) (Found: C, 47-8; H,
6.1; F, 10.8. Calc. for C,H1,O,F: C, 47.2; H, 6.2; F, 10.7%). A second fraction, b. p.
110-1 11"/2 mm. (2-4 g., ISYO),was diethyl a-$uoro-a-jZuoroacetyZmaZonate (Found: C, 46.0;
H, 4.2; F, 16-2. CgH1,O,F, requires C, 45.4; H, 5. 0; F, 16-0y0).
(c) To the enol, prepared from ethyl fluoroacetate (53 g.) and sodium hydride (12 g.) in
7 Biltz and Wittek, Ber., 1921, 54, 1035; Bock, Ber., 1922, 55, 3400.
Bruce and Huber, J . Amer. Chem. SOL, 1953, 75, 4668.
O'Neill and Pattison, ibid., 1957, 79, 1956.
lo Inman, Oesterling, and Tyczkowski, J . Amer. Chem. Soc., 1958, 80, 6533.
Palmer and McWherter, Org. Synth., 1942, Coll. Vol. I, p. 245.
l2 Blank, Mager, and Bergmann, J., 1955, 2190.
View Article Online
3288 Organic Fluorine Cowfiounds. Part X I I .
anhydrous ether (200 ml.), ethyl chloroformate (54.5 g.) in ether (50 ml.) was added a t 0" with
stirring during 15 min. The mixture was refluxed for 4 hr. and cold water added after 12 hr.
The ethereal solution was dried and distilled. The diethyl fluoromalonate (19 g., 21%) was
obtained, having b. p. 75-80"/4-5 mm., nDZ8 1.4032 (Found: C, 47.5; H, 6.2; F, 10.7%).
Another fraction (8 g.) boiled a t 110-111"/2 mm. after two distillations, and had n D 2 8 1.4180.
It was mainly ethyl a-fluoro-a-fluoroacetylmalonate,but contained a second substance poorer
in fluorine, probably triethyl fluoromethanetricarboxylate ; on hydrolysis with a slight excess
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of alcoholic potassium hydroxide a t room temperature i t gave crystalline dipotassium fluoro-
malonate. Treatment of an aqueous solution of this salt with 1 mol. of hydrochloric acid gave
hydrated potassium hydrogen fluoromalonate, which, after recrystallisation from water, lost
water when heated a t 120-130" and decomposed a t 180", and on treatment with an excess of
acid, followed by thorough extraction with ether, afforded fluoromalonic acid, m. p. 135-136"
(lit.,l 135,8-136*5"). With concentrated aqueous ammonia, the higher-boiling fraction gave
a product, m. p. 199" (from water), identified as Juoromalondiamide, by mixed m. p. (cf.
below) and the X-ray powder diagram (Found: C, 30.2; H, 3.9; F,15.9. C,H,O,N,F requires
C, 30.0; H, 4.2; F,16.0%).
The formation of triethyl fluoromethanetricarboxylate was avoided and pure diethyl
a-fluoro-a-fluoroacetylmalonate obtained when ethyl sodiofluoroacetate in ethereal suspension
was added to the ethyl chloroformate.
Fluoromalondiamide, prepared by treating the pure ester with excess of aqueous concen-
trated ammonia, as described above, had m. p. 198-199" (from water),, ,v (potassium bromide
pellet) 3400, 3200, 1700 (all vs), 1450s, 1420vs, 1320s, 1115vs, 1075vs, 815, 795, 700s,br cm.-l
(Found: C, 30.3; H , 4.2; N, 23-3; F,15.8. Calc. for C,H,O,N,F: C, 30.0; H, 4.2; N,23-3; F,
l6-OyO).
2-EthyZthio-5-fluoro-4,6-dihydroxypyrimidine(I).-A mixture of ethyl fluoromalonate
(12 g.), S-ethylisothiouronium bromide (12.5 8.) and 2hl-sodium methoxide (68 ml.) was kept
a t 28-30' for 4 days. The methanol was distilled off i n vacuo and the residue dissolved in a
little water and acidified with hydrochloric acid. Recrystallisation from aqueous alcohol
gave theproduct (12 g., 95y0),m. p. 215-220" (decomp.) (Found: C, 38.1; H, 4.1. C,H,O,N,FS
requires C, 37.9; H, 3.7%).
FZuor~acetyZurea.~~-Fluoroacetylbromide (40 g.), urea (17 g.), benzene (100 ml.), and
concentrated sulphuric acid (1 drop) were refluxed with vigorous stirring for 12 hr. The solid
(22 g., 65%) was filtered off, washed with benzene, digested with cold water, and collected.
Crystallised from dimethylformamide, it had m. p. 216-218" (Found: C, 30.3; H, 4.3.
C,H,O,N,F requires C, 30.0; H, 4.2%).
With oxalyl bromide a solid product was obtained which, however, did not give 5-flUOrO-
barbituric acid when heated in boiling tetrahydronaphthalene.
5-Fluorobarbituric Acid (11).-Urea (3 g.), ethyl fluoromalonate (9 g.), and rvx-sodium meth-
oxide (60 ml.) were refluxed for 5 hr., then kept for 1 2 hr. A solid precipitate was filtered off,
dissolved in a little water, and acidified with hydrochloric acid. 5-Fluorobarbituric acid
crystallised and, recrystallised from glacial acetic acid, had m. p. >260° (decomp.) (1 g., 16%)
(Found: C, 32.9; H, 2.1; F, 13.0. C,H,O,N,F requires C, 32.9; H, 2.1; F, 13.0%).
5-lZoo~o-4,6-dihydroxy-2-me~hyZ~yrimidine (111).-To a solution of acetamidine hydro-
chloride (2 g.) in 2hl-methanolic sodium methoxide (20 ml.), diethyl fluoromalonate (3.5 g.) was
added, and the mixture kept overnight. The solvent was removed under reduced pressure and
the residue dissolved in a little water. On acidification with hydrochloric acid, the product
(1.5 g., 53%) crystallised in fine prisms. It was purified by dissolution in dilute sodium
hydroxide solution, treatment with charcoal, filtration, and acidification of the filtrate. It
decomposed above 300" (Found: C, 41.5; H, 3.5; F, 12.4. C,H,02N,F requires C, 41.6;
H, 3.5; F, 13-2%),and had .A,, (in ethanol) 262 mp (log E 3.96), vmX. (in potassium bromide)
3410, 2800, 2700, 168Ovs(CO), 1552, 1450, 1317, 1186, 1050 (C-F), 950, 780, 752 cm.-l.
2-Amino-5-fluoro-4,6-dihydroxypyrimidine (IV).-Diethy1 fluoromalonate (14 g.) and
guanidine hydrochloride (7.5 g.) in 2~-sodiummethoxide in methanol (80 c.c.) were kept a t
room temperature, with occasional shaking, for 48 hr., then evaporated under reduced pressure.
The residue was taken up in water and acidified with hydrochloric acid. The precipitate was
redissolved in sodium hydroxide solution, treated with charcoal until the filtrate was colourless,
l3 Cf. Stoughton, J . Org. Chem., 1938, 2, 514.
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[1959] The Chemistry of the Aristolochia Species. Part I V . 3289
and precipitated with acid. After filtration and washing with water, alcohol and ether, the
yield of pyrimidine was 5.5 g. (48%) (Found: C, 32.9; H, 3-0. C4H,0,N,F requires C, 33.1;
H, 2.8%).
This work was sponsored by the United States National Institute of Health.
DEPARTMENT OF ORGANIC CHEMISTRY,HEBREWUNIVERSITY,JERUSALEM.
SCIENTIFIC DEPARTMENT, MINISTRYOF DEFENCE,
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TEL-AVIV, ISRAEL. [Received, January 23rd, 1959.1
