CYCLIZATION DICHOTOMY OF ESTERS OF 3-UREIDO-2-CYANO-2-PROPENOIC AND 3-UREIDO-2-ACYL-2-PROPENOIC ACIDS

Article abstract of DOI:10.1135/cccc19941841

The preparation of E and Z isomers of 3-ureido-2-cyano-2-propenoates Ia-Id and their base-catalyzed isomerization and cyclization to 5-carboxycytosine derivatives IIa-IIf and 5-cyanouracil derivatives IIIa and IIIb is described.Also described is the preparation of 3-ureido-2-acyl-2-propenoates Va-Vd and their base-catalyzed cyclization to 5-carboxy-2(1H)-pyrimidone derivatives VIa-VIc and 5-acyluracils VIIa-VIIc.

Full text of DOI:10.1135/cccc19941841

Cyclization Dichotomy
1841
CYCLIZATION DICHOTOMY OF ESTERS OF 3-UREIDO-2-CYANO-
2
-PROPENOIC AND 3-UREIDO-2-ACYL-2-PROPENOIC ACIDS
Miroslav LEDVINA and †Jiri FARKAS
Institute of Organic Chemistry and Biochemistry,
Academy of Sciences of the Czech Republic, 166 10 Prague 6, The Czech Republic
Received January 28, 1994
Accepted April 20, 1994
The preparation of E and Z isomers of 3-ureido-2-cyano-2-propenoates Ia – Id and their base-cata-
lyzed isomerization and cyclization to 5-carboxycytosine derivatives IIa – IIf and 5-cyanouracil deri-
vatives IIIa and IIIb is described. Also described is the preparation of 3-ureido-2-acyl-2-propenoates
Va – Vd and their base-catalyzed cyclization to 5-carboxy-2(1H)-pyrimidone derivatives VIa – VIc
and 5-acyluracils VIIa – VIIc.
Some time ago we described1,2 E and Z isomers of N′-substituted methyl 3-ureido-2-
methyl-2-propenoates and their isomerization and cyclization to 3-substituted 5-methyl-
uracils. We also described E and Z isomers of N′-susbtituted methyl 3-sulfamido-
2
4
-methyl-2-propenoates and their isomerization and cyclization to derivatives of
-methyl-2H-1,2,6-thiadiazin-3(6H)-one 1,1-dioxide, a structural analog of thymine.
The present communication concerns the configuration on the C=C bond in, and cycli-
zation reactions of, esters of 3-ureido-2-cyano-2-propenoic acids Ia – Id and of 3-ureido-
2
-acyl-2-propenoic acids Va – Vd, and their utilization in the synthesis of 5-cyanouracil
3
and 5-acyluracils. Our interest was aroused by a paper reporting antiviral effects of
1
-(2-deoxy-β-D-erythro-pentofuranosyl) derivatives of some 5-substituted uracils.
The base-catalyzed cyclization of ethyl 3-ureido-2-cyano-2-propenoate (Ia) and its
N′-substituted derivatives represents a currently used approach to derivatives of 5-car-
4
–6
boxycytosine IIf (refs ). Upon treatment with sodium ethoxide, ethyl 3-ureido-2-ace-
tyl-2-propenoate (Va) is cyclized to 5-ethoxycarbonyl-4-methylpyrimidin-2(1H)-one (VIa)
whereas in aqueous potassium hydroxide affords 5-acetyluracil (VIIa) in a low yield
7
,8
(
25%) (refs ). The starting ureido derivatives Ia – Id and Va – Vd are well accessible
4
,5,9,10
by Whitehead synthesis
, i.e. reaction of N,N′-bis(N-alkylcarbamoyl)formamidi-
nes, or directly by condensation of ureas and ethyl orthoformate with compounds con-
taining an active CH group (derivatives of malonic acid, ethyl acetoacetate or ethyl
2
nitroacetate).
In the reaction of urea and ethyl orthoformate with ethyl cyanoacetate we obtained
the E isomer (E)-Ia as the sole product. The same reaction with methyl cyanoacetate
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

1
842
Ledvina, Farkas:
gave a mixture of isomers (E)-Ib and (Z)-Ib in the ratio 5 : 2. N-Methylurea and ethyl
orthoformate reacted with ethyl cyanoacetate to give a 5 : 9 mixture of isomers (E)-Ic
and (Z)-Ic, which was separated by chromatography on silica gel. Under the same con-
ditions, the reaction with methyl cyanoacetate gave only the isomer (Z)-Id.
In comparison with N′-substituted methyl 3-ureido-2-methyl-2-propenoates and
methyl 3-sulfamido-2-methyl-2-propenoates, compounds Ia – Id are configurationally
less stable and rapidly isomerize in solution when heated or treated with base. In
boiling water, after 30 min, the isomer (E)-Ia afforded a mixture of E and Z isomers
(
5 : 4); after 30 min at 100 °C in 50% aqueous methanol isomer (Z)-Id gave a 1 : 1
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

Cyclization Dichotomy
1843
mixture of (E)-Id and (Z)-Id. Treatment of (E)-Ic with 2 M ethanolic sodium ethoxide at
room temperature for 1 min gave also a 1 : 1 mixture of (E)-Ic and (Z)-Ic.
The configuration at the C=C double bond in compounds Ia – Id was determined on
the basis of chemical shifts of vinyl protons and the proton of the nonterminal NH
group, similarly as in the case of methyl 3-(N′-alkylureido)-2-methyl-2-propenoates de-
1
scribed by us . The E : Z isomer ratio in the mixtures was determined by integration of
vinyl proton signals after exchange of interacting NH protons in deuterium oxide. The
1
H NMR spectra of compounds Ia – Id are given in Table I.
Taking into account the proven base-catalyzed E/Z isomerization of compounds Ia – Id,
we may expect that configuration at the C=C bond will not affect the direction of the
cyclization and that the decisive factor will be only the difference in reactivity of the
4
nitrile and alkoxycarbonyl groups. In accord with the literature , we observed that cycliza-
tion of ethyl ester (E)-Ia in boiling 2 M solution of sodium ethoxide afforded only the
cytosine derivative IIa. Also ethyl ester (Z)-Ic on treatment with 2 M sodium ethoxide at
room temperature gave cytosine derivative IIc as the sole product. On the other hand,
cyclization of the above-mentioned isomeric mixture of methyl esters (E)-Ib and (Z)-Ib
in 2 M sodium methoxide at reflux furnished a mixture of cytosine derivative IIb and
uracil derivative IIIa in the ratio 5 : 3; under the same conditions, methyl ester (Z)-Id
afforded a mixture of cytosine derivative IId and uracil derivative IIIb in the ratio 15 : 1.
Reaction of a mixture of methyl esters (E)-Ib and (Z)-Ib with sodium 3-methylbutoxide
in boiling 3-methylbutanol led only to the cytosine derivative IIe. We assume that in
TABLE I
1
H NMR parameters of compounds Ia – Id, for conditions see Experimental
Chemical shifts, ppm
Coupling constants, Hz
Compound
CH=
CONHCH
RNHCO
CH NH
J(CH=,NH) J(NH,CH3)
3
a
i
1
3.0
E-Ia
8.51 d
8.11 d
8.44 d
8.08 d
8.58 d
8.17 d
8.62 d
8.15 d
10.10 d
10.63 d
10.22 d
10.53 d
9.93 d
6.90 s
–
–
–
–
b
i
Z-Ia
6.90 s
13.0
13.0
13.0
13.0
13.0
13.0
13.0
c
i
E-Ib
7.40 s
–
–
d
i
Z-Ib
7.40 s
–
–
e
E-Ic
6.96 m
7.81 m
6.93 m
7.89 m
2.86 d
2.83 d
2.83 d
2.81 d
4.6
4.6
4.6
4.6
f
Z-Ic
10.62 d
9.96 d
g
E-Id
h
Z-Id
10.62 d
a
b
Other signals: 1.31 t, 3 H, J = 7.0 (CH CH O); 4.24 q, 2 H, J = 7.0 (CH CH O). 1.35 t, 3 H, J = 7.0
3
2
3
2
c
d
e
(
3
2
CH CH O); 4.29 q, 2 H, J = 7.0 (CH CH O). 3.74 s, 3 H (CH O). 3.78 s, 3 H (CH O). 1.34 t,
3 2 3 2 3 3
H, J = 7.0 (CH CH O); 4.26 q, 2 H, J = 7.0 (CH CH O). 1.35 t, 3 H, J = 7.0 (CH CH O); 4.28 q,
3 2 3 2 3 2
H, J = 7.0 (CH CH O). 3.78 s, 3 H (CH O). 3.82 s, 3 H (CH O). 2 H.
f
g
h
i
3
2
3
3
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

1
844
Ledvina, Farkas:
the first reaction step the methyl ester Ib is transesterified into the 3-methylbutyl ester
which then is unequivocally cyclized to give compound IIe. In connection with the
1
1,12
described
cyclization of ethyl 3-(S-ethylthioureido)-2-cyano-2-propenoate to
2
-ethylthio-5-cyano-4(3H)-pyrimidone and of ethyl 3-acetamidino-2-cyano-2-prope-
noate to 5-cyano-2-methyl-4(3H)-pyrimidone by treatment with aqueous sodium hy-
droxide, we performed under comparable conditions cyclization of ethyl ester (E)-Ia.
Reaction of compound (E)-Ia in boiling 0.1 M NaOH gave 51% of complex of uracil
derivative IIIa with one molecule of urea, together with 5% of cytosine derivative IIf.
The uracil derivative IIIa was liberated from the complex by treatment with Dowex 1
in the carbonate form. We prepared the same complex from an equimolecular mixture
of compound IIIa and urea by crystallization from water. Attempted cyclization of a
mixture of (E)-Ib and (Z)-Ib by sodium acetate in boiling acetic anhydride afforded a
mixture of E and Z isomers of IV in the ratio 6 : 5. A similar cleavage was observed
1
3
with methyl glyoxylate semicarbazone .
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

Cyclization Dichotomy
1845
3
-Ureido-2-acyl-2-propenoates Va – Vd were prepared by condensation of urea and
ethyl orthoformate with the corresponding 3-keto esters (ethyl acetoacetate, methyl ace-
toacetate, ethyl 3-oxopentanoate and ethyl 3-oxo-6-heptenoate). We did not succeed in
1
using H NMR spectroscopy to determine configuration at the C=C bond in the ob-
tained compounds Va – Vd. The spectra of these compounds did not exhibit doubled
signals corresponding to E/Z isomer mixtures and after UV-irradiation in ethanol the
spectrum of Va was identical with that of the unirradiated compound. Spectrum of
compound Vd corresponds to a mixture of geometric isomers at the inner C=C bond.
Upon treatment of ethyl ester Va in boiling 0.1 M sodium ethoxide solution we ob-
7
tained 5-acetyluracil (VIIa; 8%), in addition to compound VIa (62%) described as the
reaction product. In contrast with methyl 3-ureido-2-cyano-2-propenoate (Ib), no mar-
kedly higher yields of the uracil derivative VIIa (15%) were observed in the cyclization
of methyl ester Vb. In this reaction we isolated another product whose composition
(
C H N O ) corresponded to a condensation dimer of the starting compound Vb. We
14 18 4 7
prepared the uracil derivative VIIa in 41% yield by cyclization of ethyl ester Va by
treatment with Dowex 1 in the carbonate form. As the side-product we obtained com-
pound VIa (10%). Cyclization of compounds Vc or Vd in 0.1 M NaOH at room tempera-
ture afforded a mixture of compound VIb and uracil derivative VIIb or a mixture of
compound VIc and uracil derivative VIIc in the ratio 2 : 1.
The mentioned cyclization reactions of easily accessible alkyl 3-ureido-2-cyano-2-
propenoates and 3-ureido-2-acyl-2-propenoates leading to the respective 5-cyanouracil
and 5-acyluracil derivatives represent an alternative to cyclizations of 3-ethoxy-
N-ethoxycarbonyl-2-cyano-2-propenoyl amide and 2-acyl-3-ethoxy-N-ethoxycarbonyl-
1
4,15
2
5
5
-propenoyl amide described by Shaw
, as well as to the preparation of
1
0
-cyanouracil by conversion of 5-cyanocytosine by Sandmeyer reaction from
-aminouracil , or by reaction of 5-iodouracil with CuCN. Reaction of 5-bromouracil
with NaCN affords predominantly 6-cyanouracil . 1-Substituted 5-acyluracils can also
be obtained by successive lithiation, acylation and oxidation of appropriate 5,6-dihydro-
1
6
17
1
8
1
9
uracils .
EXPERIMENTAL
The melting points were determined on a Kofler block and are uncorrected. 1H NMR spectra were
measured on a Tesla BS-467 instrument (60 MHz) in a mixture of deuteriochloroform and
hexadeuteriodimethyl sulfoxide (unless stated otherwise) with tetramethylsilane as internal standard.
1
Chemical shifts are given in ppm (δ-scale) and coupling constants (J) in Hz. The H NMR spectra of
compounds Ia – Id are given in Table I; the E : Z isomer ratios in the mixtures were determined from
integration of vinyl proton signals after exchange of the interacting NH protons with deuterium
oxide. UV spectra were recorded on a Specord UV-VIS instrument and IR spectra on a UR 10 spec-
−1
trometer (both Zeiss, Jena, Germany). Wavenumbers are given in cm . Thin-layer chromatography
was performed on Silufol UV254 and column chromatography on silica gel Silpearl (both Kavalier,
Votice, The Czech Republic). Analytical samples were dried at 25 °C and 6.5 Pa for 8 h.
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

1
846
Ledvina, Farkas:
Ethyl (E)-2-Cyano-3-ureido-2-propenoate ((E)-Ia)
A mixture of urea (6.0 g, 100 mmol), ethyl cyanoacetate (12.43 g, 110 mmol) and ethyl orthoformate
(
16.0 g, 112 mmol) was refluxed for 8 h. After cooling, the solid reaction mixture was triturated with
ethyl acetate (50 ml), the solid portion was collected on filter and washed with ethyl acetate and
ether; yield 12.1 g (66%) of compound (E)-Ia. Crystallization from 80% aqueous ethanol afforded (E)-Ia
4
(
8.23 g, 45%) as the only product; m.p. 177 – 199 °C (reported m.p. 215 °C for a noncrystallized
product). For C H N O (183.1) calculated: 45.88% C, 4.95% H, 22.94% N; found: 45.69% C,
7
9
3
3
5
.12% H, 22.75% N.
Methyl 2-Cyano-3-ureido-2-propenoates ((E)-Ib and (Z)-Ib)
A mixture of urea (6.0 g, 100 mmol), methyl cyanoacetate (10.89 g, 110 mmol) and ethyl orthofor-
mate (18 ml, 108.2 mmol) was refluxed for 8 h. The reaction mixture was worked up as described
for the preparation of compound Ia; yield 11.05 g (65%) of compound Ib. Crystallization from 50%
aqueous methanol afforded 7.82 g (46%) of a 5 : 2 mixture of (E)-Ib and (Z)-Ib, m.p. 179 – 201 °C
4
(
reported m.p. 215 °C). For C H N O (169.1) calculated: 42.58% C, 4.17% H, 24.84% N; found:
6
7
3
3
4
2.52% C, 4.37% H, 24.68% N.
Ethyl 2-Cyano-3-(N′-methylureido)-2-propenoates ((E)-Ic and (Z)-Ic)
A mixture of N-methylurea (3.7 g, 50 mmol), ethyl cyanoacetate (6.22 g, 55 mmol) and ethyl ortho-
formate (15 ml, 90.2 mmol) was refluxed for 6 h. After cooling, the solid reaction mixture was tri-
turated with benzene (20 ml), the solid portion was collected on filter and washed with benzene;
yield 5.98 g (61%) of compound Ic. Crystallization from ethyl acetate afforded a mixture of E and Z
6
isomers of Ic (3.7 g, 37%) in the ratio 5 : 9; m.p. 145 – 159 °C (reported m.p. 153 – 158 °C). The
obtained mixture was separated by column chromatography on silica gel (600 g) in chloroform–ethyl
acetate (3 : 1).
The UV-absorbing fraction of higher RF value afforded 1.95 g (20%) of (Z)-Ic, m.p. 146 – 156 °C
−1
3
1
(
ethyl acetate). IR spectrum (chloroform, 3 . 10−3 mol l ): 3 452 (N −H, free), 3 286 (N −H, intra-
−1
−1
3
1
molecularly hydrogen bonded); (chloroform, ≈ 10 mol l ): 3 451 (N −H, free), 3 304 (N −H, intra-
3
molecularly hydrogen bonded); 3 224 (N −H, intermolecularly hydrogen bonded); 2 239, 2 227,
2
219 (C≡N); 1 734 (amide I); 1 693 (C=O, COOC H , intramolecularly hydrogen bonded); 1 621
2 5
3
1
(
C=C); 1 559 (amide II, N −H); 1 538 (N −H). For C H N O (197.1) calculated: 48.70% C,
8
11
3
3
5
.62% H, 21.31% N; found: 48.95% C, 5.58% H, 21.09% N.
The UV-absorbing fraction of lower RF value afforded 1.032 g (11%) of (E)-Ic, m.p. 155 – 171 °C
−
3
−1
3
1
(
3
ethyl acetate). IR spectrum (chloroform, 3 . 10 mol l ): 3 450 (N −H, free); 3 412 (N −H, free);
3
−1
−1
300 (N −H, bonded); (chloroform, ≈ 10 mol l ): 3 411 (N−H, free), 3 388, 3 297, 3 224 (N−H,
bonded); 2 225 (C≡N); 1 741 (amide I); 1 722 (C=O, COOC H ); 1 625 (C=C); 1 552, 1 539 (amide II).
2
5
For C H N O (197.1) calculated: 48.70% C, 5.62% H, 21.31% N; found: 48.90% C, 5.62% H,
8
11
3
3
2
1.08% N.
Methyl (Z)-2-Cyano-3-(N′-methylureido)-2-propenoate ((Z)-Id)
A mixture of N-methylurea (3.7 g, 50 mmol), methyl cyanoacetate (5.45 g, 55 mmol) and ethyl
orthoformate (15 ml, 90.2 mmol) was refluxed for 6 h. The reaction mixture was worked up as de-
scribed for the preparation of compound Ic; yield 5.21 g (55%) of product. Crystallization from ethyl
acetate afforded 3.96 g (42%) of (Z)-Id, m.p. 170 – 197 °C. For C H N O (183.1) calculated:
7
9
3
3
4
5.88% C, 4.95% H, 22.94% N; found: 46.09% C, 5.20% H, 22.65% N.
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

Cyclization Dichotomy
1847
Isomerization of Ethyl (E)-2-Cyano-3-ureido-2-propenoate ((E)-Ia)
A solution of (E)-Ia (46 mg, 0.25 mmol) in water (5 ml) was boiled for 30 min. After cooling, the
1
water was evaporated and the isomer ratio was determined by H NMR spectroscopy to be (E)-Ia :
(
Z)-Ia = 5 : 4.
Isomerization of Methyl (Z)-2-Cyano-3-(N′-methylureido)-2-propenoate ((Z)-Id)
A solution of isomer (Z)-Id (47.3 mg, 0.25 mmol) in 50% methanol (5 ml) was heated at 100 °C for
0 min in a sealed ampoule. After cooling and opening the ampoule, the mixture was evaporated and
3
the E : Z isomer ratio (1 : 1) was determined as in the preceding experiment.
Isomerization of Ethyl (Z)-2-Cyano-3-(N′-methylureido)-2-propenoate ((Z)-Ic)
A solution of (Z)-Ic (39.5 mg, 0.2 mmol) in ethanolic 2 M sodium ethoxide (0.2 ml, 0.4 mmol) was
stirred at ambient temperature for 1 min, 10 min and 1 h. After the given time, ethanol (5 ml) was
added and the solution was neutralized with Dowex 50 (acid form, 2 ml). The ion exchanger was
filtered off and the filtrate was evaporated to give 36, 31 and 28 mg of a mixture of (E)-Ic and (Z)-Ic,
invariably in the ratio 1 : 1. The isomer ratio was determined as in the preceding experiments.
5
-Ethoxycarbonylcytosine (IIa)
A stirred solution of isomer (E)-Ia (1.83 g, 10 mmol) in 2 M ethanolic sodium ethoxide (10 ml,
2
0 mmol) was refluxed for 4 h. The solid reaction mixture was cooled, dissolved in ice-cold water
(
100 ml) and applied onto a column of Dowex 50 (acid form; 20 ml). After washing the column with
water (200 ml), the product was eluted with 5% aqueous ammonia (200 ml) and the eluate was taken
down. Crystallization of the residue (1.76 g, 96%) from pyridine–water (3 : 7) afforded 1.1 g (60%)
4
of compound IIa, m.p. 270 – 283 °C (decomp.). Reported m.p. 260 – 270 °C. UV spectrum (methanol):
λmax 226 and 277 nm (log ε 4.20 and 4.80).
5
-Methoxycarbonylcytosine (IIb) and 5-Cyanouracil (IIIa)
A stirred solution of a mixture of (E)-Ib and (Z)-Ib (1.69 g, 10 mmol) in 2 M methanolic sodium
methoxide (10 ml, 20 mmol) was refluxed for 4 h. The solid reaction mixture was cooled, dissolved
in ice-cold water (80 ml) and applied onto a column of Dowex 50 (acid form; 20 ml). The column
was washed with water (200 ml) and the solvent was evaporated. Crystallization of the residue
(
398 mg, 29%) from water afforded 318 mg (23%) of compound IIIa, m.p. 320 °C (decomp.). Re-
1
0
ported m.p. 319 – 320 °C. Its IR spectrum was identical with that of an authentic sample of com-
pound IIIa (ref. ).
1
0
Washing the column with 5% aqueous ammonia (200 ml) and evaporation of the solvent afforded
8
95 mg (53%) of a residue which on crystallization from pyridine–water (3 : 7) gave 665 mg (39%)
of compound IIb, m.p. 248 – 253 °C (decomp.). UV spectrum (methanol): λmax 226 and 278 nm
(
log ε 4.16 and 3.80). For C H N O (169.1) calculated: 42.58% C, 4.17% H, 24.84% N; found:
6
7
3
3
4
2.80% C, 4.43% H, 24.64% N.
5
-Ethoxycarbonyl-3-methylcytosine (IIc)
A solution of (Z)-Ic (394 mg, 2 mmol) in ethanolic 2 M sodium ethoxide (2 ml, 4 mmol) was stirred
at ambient temperature for 24 h. The solid reaction mixture was dissolved in ice-cold water (16 ml)
and the solution was applied onto a column of Dowex 50 (acid form; 20 ml). The column was eluted
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

1
848
Ledvina, Farkas:
with water (200 ml) and the eluate was evaporated: no uracil derivative IIIb was detected in the
residue. The product IIc was eluted with 5% aqueous ammonia (250 ml). Evaporation of the eluate
afforded 340 mg (86%) of a residue which was crystallized from water; yield 266 mg (68%) of com-
6
pound IIc, m.p. 230 – 235 °C (decomp.). Reported m.p. 234 – 235 °C. UV spectrum (ethanol): λ
max
2
53 and 296 nm (log ε 4.08 and 4.05).
-Methoxycarbonyl-3-methylcytosine (IId) and 5-Cyano-3-methyluracil (IIIb)
5
A stirred solution of (Z)-Id (916 mg, 5 mmol) in 2 M methanolic sodium methoxide (5 ml, 10 mmol)
was refluxed for 8 h. The solid reaction mixture was cooled, dissolved in ice-cold water (60 ml) and
applied onto a column of Dowex 50 (acid form; 50 ml). The column was washed with water
(
500 ml), the eluate was evaporated and the residue was extracted with ethyl acetate (2 × 2 ml). The
insoluble residue (47 mg; 6%) was crystallized from ethanol to give 25 mg (3%) of compound IIIb,
m.p. 219 – 225 °C. UV spectrum (methanol): λmax 215 and 273 nm (log ε 4.02 and 4.04). IR spec-
trum (KBr): 3 265, 3 209 (N−H); 2 246 (C≡N); 1 729, 1 658 (C=O); 1 634 (C=C). For C H N O
6
5
3
2
(
151.0) calculated: 47.66% C, 3.33% H, 27.80% N; found: 47.79% C, 3.61% H, 27.50% N. The pro-
duct IId was then eluted with 5% aqueous ammonia (500 ml). Evaporation of the solvent afforded
33 mg (91%) of residue which on crystallization from water afforded 652 mg (71%) of compound
8
IId, m.p. 245 °C. UV spectrum (methanol): λmax 206, 250 and 295 nm (log ε 3.91, 4.24 and 4.20).
For C H N O (183.1) calculated: 45.88% C, 4.95% H, 22.94% N; found: 45.64% C, 5.19% H,
7
9
3
3
2
2.87% N.
5
-(3-Methylbutoxycarbonyl)cytosine (IIe)
A
mixture of (E)-Ib and (Z)-Ib (169 mg, 1 mmol) was dissolved in a 0.5 M solution of sodium 3-methyl-
butoxide in 3-methylbutanol (4 ml, 2 mmol) and refluxed for 90 min under stirring. The solid reac-
tion mixture was cooled and dissolved in 60% ethanol (20 ml) under ice-cooling. The solution was
applied onto a column of Dowex 50 (acid form; 10 ml) and the column was then washed with 60%
ethanol (150 ml). The product was eluted with 5% ammonia solution in 20% ethanol (150 ml).
The eluate was taken down and the residue (208 mg; 92%) was crystallized from pyridine–water (3 : 7)
to give 142 mg (63%) of compound IIe, m.p. 300 °C (decomp.). UV spectrum (methanol): λmax 226 and
2
77 nm (log ε 4.16 and 3.75). For C H N O (225.1) calculated: 53.30% C, 6.71% H, 18.65% N;
10 15 3 3
found: 53.23% C, 7.01% H, 18.94% N.
5
-Carboxycytosine (IIf) and 5-Cyanouracil (IIIa)
A solution of (E)-Ia (3.63 g, 20 mmol) in 0.1 M NaOH (500 ml, 50 mmol) was refluxed for 30 min.
After cooling, the solution was applied onto a column of Dowex 50 (acid form; 60 ml). The column
was washed with water (500 ml), the eluate was evaporated and the residue was extracted with
acetone (2 × 10 ml). The insoluble portion (998 mg; 51%) consisted of equimolecular complex of
5
-cyanouracil IIIa and urea, m.p. 250 – 320 °C. After crystallization from water, the compound
(
775 mg; 39%) melted at 253 – 320 °C. UV spectrum (methanol): λmax 214 and 273 nm (log ε 4.02
and 4.04). IR spectrum (dimethyl sulfoxide): 2 237 (C≡N); 1 770, 1 724, 1 689, 1 629. Both the UV
and IR spectrum are identical with those of an authentic sample prepared by crystallization of an
equimolar mixture of compound IIIa and urea from water. For C H N O . CH N O (197.1) calcu-
5
3
3
2
4
2
lated: 36.53% C, 3.58% H, 35.52% N; found: 36.75% C, 3.78% H, 35.76% N.
A solution of the equimolar complex of 5-cyanouracil IIIa and urea (197 mg, 1 mmol) in water
(
10 ml) was stirred with Dowex 1 (carbonate form, 3 ml) for 20 min at room temperature. The ion
exchanger was filtered off, washed with water and the filtrate was concentrated to give 60 mg
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

Cyclization Dichotomy
1849
(
100%) of urea. The ion exchanger was then stirred with 5% formic acid (20 ml) for 20 min, filtered
and washed with 5% formic acid (30 ml). Evaporation of the filtrate afforded 136 mg (100%) of
1
0
compound IIIa, identical (m.p., UV and IR spectrum) with an authentic sample .
Compound IIf was eluted from the column with 5% sodium hydrogen carbonate solution and pre-
cipitated from the solution by addition of concentrated acetic acid. The precipitate was centrifuged
and washed with water and methanol. Yield 168 mg (5%) of compound IIf, m.p. 257 °C (decomp.).
2
0
Reported m.p. 256 °C. UV spectrum (water): λmax 221 and 278 nm (log ε 4.10 and 3.96).
Methyl 3-Acetylamino-2-cyano-2-propenoate (IV)
Compound Ib (169 mg, 1 mmol) in acetic anhydride (1 ml) was refluxed for 3 h. Sodium acetate
(
164 mg, 2 mmol) was added and the reflux was continued for 15 min. After cooling, the mixture
was poured into ice-cold water (20 ml) and the suspension was extracted with chloroform (3 × 50 ml).
The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated and the
residue was crystallized from benzene to give 112 mg (67%) of a mixture of E and Z isomers IV
1
(
5 : 6); m.p. 115 – 133 °C. H NMR spectrum (deuteriochloroform); (E)-IV: 2.38 s, 3 H (NCOCH );
3
3
.83 s, 3 H (COOCH ); 8.64 d, 1 H, J(CH,NH) = 13.0 (−CH=); 10.84 d, 1 H, J(CH,NH) = 13.0
3
(
NH); (Z)-IV: 2.36 s, 3 H (NCOCH ); 3.86 s, 3 H (COOCH ); 8.15 d, 1 H, J(CH,NH) = 12.0 (−CH=);
3
3
9
1
.37 d, 1 H, J(CH,NH) = 12.0 (NH). For C H N O (168.2) calculated: 49.98% C, 4.79% H,
6.66% N; found: 50.26% C, 5.06% H, 16.82% N.
7
8
2
3
Ethyl 2-Acetyl-3-ureido-2-propenoate (Va)
4
The title compound was prepared by the described procedure and was crystallized from ethanol, m.p.
4
1
1
2
=
78 – 195 °C (reported m.p. 194 – 195 °C). H NMR spectrum: 1.29 t, 3 H, J = 7.0 (CH CH O);
3 2
.98 s, 3 H (CH CO); 4.21 q, 2 H, J = 7.0 (CH CH O); 7.01 s, 2 H (NH ); 8.58 d, 1 H, J(CH,NH)
12.0 (−CH=); 11.60 d, 1 H, J(CH,NH) = 12.O (NH).
3
3
2
2
Methyl 2-Acetyl-3-ureido-2-propenoate (Vb)
A stirred mixture of urea (6.0 g, 100 mmol), methyl acetoacetate (11.6 g, 100 mmol) and ethyl orthofor-
mate (20 ml, 120.2 mmol) was refluxed for 6 h. The mixture was cooled and the deposited com-
pound was filtered and washed with ethyl acetate and ether; yield 10.63 g (58%). Crystallization
1
from methanol afforded 6.65 g (36%) of compound Vb, m.p. 195 – 217 °C. H NMR spectrum: 3.32 s,
3
1
H (CH CO); 3.71 s, 3 H (CH O); 7.25 s, 2 H (NH ); 8.53 d, 1 H, J(CH,NH) = 12.5 (−CH=); 11.53 d,
3 3 2
H, J(CH,NH) = 12.5 (NH). For C H N O (186.1) calculated: 45.14% C, 5.41% H, 15.04% N;
7
10
2
4
found: 45.36% C, 5.61% H, 15.23% N.
Ethyl 2-Propionyl-3-ureido-2-propenoate (Vc)
A stirred mixture of urea (1.2 g, 20 mmol), ethyl 3-oxopentanoate (2.9 g, 20 mmol) and ethyl ortho-
formate (4 ml, 24.0 mmol) was refluxed and then worked up as described for the preparation of com-
pound Vb. The product (1.25 g; 30%) was crystallized from ethanol to give 830 mg (20%) of
1
compound Vc, m.p. 186 °C. H NMR spectrum: 1.05 t, 3 H, J = 7.5 (CH CH CO); 1.29 t, 3 H, J = 7.0
3
2
(
CH CH O); 2.29 q, 2 H, J = 7.5 (CH CH CO); 4.20 q, 2 H, J = 7.0 (CH CH O); 6.92 s, 2 H (NH );
3 2 3 2 3 2 2
8
.57 d, 1 H, J(CH,NH) = 13.0 (−CH=); 11.67 d, 1 H, J(CH,NH) = 13.0 (NH). For C H N O
9 14 2 4
(
214.1) calculated: 50.44% C, 6.59% H, 13.07% N; found: 50.67% C, 6.47% H, 13.34% N.
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

1
850
Ledvina, Farkas:
Ethyl 3-Oxo-2-ureidomethylene-6-heptenoate (Vd)
A stirred mixture of urea (4.8 g, 80 mmol), ethyl 3-oxo-6-heptenoate (13.6 g, 80 mmol) and ethyl
orthoformate (16 ml, 96.2 mmol) was refluxed for 6 h and then worked up as described for the
preparation of compound Vb. The product (6.0 g; 31%) was crystallized from ethyl acetate to give 4.59 g
1
(
24%) of compound Vd, m.p. 139 – 161 °C. H NMR spectrum (mixture of geometric isomers): 1.26 m,
6
5
8
H (2 × CH CH O); 2.28 m, 4 H (2 × CH ); 2.95 m, 4 H (2 × CH CO); 4.19 m, 4 H (2 × CH CH O);
3 2 2 2 3 2
.22 m, 4 H (2 × CH =CH−); 6.03 m, 2 H (2 × CH =CH−); 7.51 s, 4 H (2 × NH ); 8.39 d, 1 H and
2
2
2
.47 d, 1 H, J(CH,NH) = 7.0 (−CH=); 10.21 d, 1 H and 11.45 d, J(CH,NH) = 7.0 (NH). For
C H N O (240.1) calculated: 54.97% C, 6.71% H, 11.66% N; found: 54.76% C, 6.62% H, 11.64% N.
1
1
16
2
4
5
-Ethoxycarbonyl-4-methylpyrimidin-2(1H)-one (VIa) and 5-Acetyluracil (VIIa)
A. Compound Va (1 g, 5 mmol) in 1 M ethanolic sodium ethoxide (10 ml, 10 mmol) was refluxed
with stirring for 30 min. After cooling, the stirred mixture was mixed with cold water (70 ml) and
neutralized with concentrated acetic acid. The separated product was filtered, washed with water and
dried. Crystallization from 80% ethanol afforded 560 mg (62%) of compound VIa, m.p. 257 °C (de-
7
comp.). Reported m.p. 248 – 250 °C. UV spectrum (ethanol–0.1 M HCl, 1 : 1): λ
240 and 303 nm
max
(
log ε 4.34 and 3.70); (ethanol–0.1 M NaOH, 1 : 1): λmax 260 nm (log ε 4.35).
The mother liquors after separation of compound VIa were poured on a column of Dowex 50 (acid
form; 20 ml). Elution with water (150 ml) and evaporation of the eluate afforded 58 mg (8%) of
product which on crystallization from water gave 45 mg (6%) of compound VIIa, m.p. 276 – 293 °C
7
(
(
decomp.). Reported m.p. 294 °C. UV spectrum (ethanol–0.1 M HCl, 1 : 1): λmax 227 and 282 nm
log ε 4.09 and 4.11); (ethanol–0.1 M NaOH, 1 : 1): λmax 249 and 310 nm (log ε 4.06 and 4.29).
B. A solution of compound Va (1.0 g, 5 mmol) in 80% ethanol (200 ml) was pumped in a closed
cycle through a column of Dowex 1 (carbonate form; 20 ml) until the starting compound Va disap-
peared. The reaction was monitored by thin-layer chromatography on silica gel in ethyl acetate–
acetone–ethanol–water (40 : 2 : 2 : 1). The ion exchanger was stirred with 5% formic acid (100 ml),
filtered off, washed with 5% formic acid (100 ml) and the filtrate was concentrated. The residue was
extracted with boiling water (3 × 5 ml) and the insoluble material was washed with ethanol and
dried. Yield 209 mg (22%) of compound decomposing above 210 °C; its elemental composition
corresponded to the condensation dimer of the starting compound Va. For C H N O (382.4) calcu-
1
6
22
4
7
lated: 50.23% C, 5.80% H, 14.65% N; found: 50.51% C, 5.55% H, 14.94% N.
The combined extracts were applied onto a column of Dowex 50 (acid form; 15 ml) and the pro-
duct was eluted with water (200 ml). Evaporation of the eluate and crystallization of the residue (318 mg;
4
1%) from water afforded 271 mg (35%) of compound VIIa, identical (m.p. and UV spectrum) with
the compound prepared by procedure A.
Elution of the column with 5% solution of pyridine (200 ml) and evaporation of the eluate gave
8
8 mg (10%) of compound VIa, identical (m.p. and UV spectrum) with the compound prepared by
procedure A.
5-Acetyluracil (VIIa)
A solution of compound Vb (930 mg, 5 mmol) in 0.1 M methanolic sodium methoxide (10 ml,
1
0 mmol) was refluxed for 1 h. After cooling, the mixture was stirred with ice-cold water (70 ml),
neutralized with concentrated acetic acid and set aside at 3 °C overnight. The separated product was
filtered and washed with water (163 mg) and the mother liquors were applied onto a column of
Dowex 50 (acid form; 20 ml). Elution of the column with water (150 ml), evaporation of the solvent
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

Cyclization Dichotomy
1851
and crystallization of the residue (118 mg, 15%) from water afforded 68 mg (9%) of compound VIIa,
identical (m.p. and UV spectrum) with the compound VIIa prepared in the preceding experiments.
Elution of the column with 5% aqueous pyridine (150 ml) and evaporation of the eluate gave 140 mg
of material which was combined with the product deposited from the reaction mixture after the neu-
tralization with acetic acid. The combined portions (303 mg) were dissolved in 80% ethanol, the solution
was mixed with silica gel (500 mg) and after evaporation chromatographed on a column of silica gel
(
1
50 g) in ethyl acetate–acetone–ethanol–water (40 : 2 : 2 :1). The obtained crystalline material (171 mg,
9%) decomposed above 210 °C and its elemental composition corresponded to that of the conden-
sation dimer of the starting compound Vb. For C H N O (354.1) calculated: 47.43% C, 5.12% H,
1
4
18
4
7
1
5.81% N; found: 47.21% C, 5.37% H, 15.94% N.
5
-Ethoxycarbonyl-4-ethylpyrimidin-2(1H)-one (VIb) and 5-Propionyluracil (VIIb)
A mixture of compound Vc (865 mg, 4.12 mmol) and 0.1 M NaOH (80 ml, 8 mmol) was shaken at
room temperature for 30 min and then neutralized with concentrated acetic acid. The precipitated
product was filtered, washed with water, dried (382 mg, 47%) and crystallized from ethanol to give
3
24 mg (40%) of compound VIb, m.p. 207 °C. UV spectrum (ethanol–0.1 M HCl, 1 : 1): λmax 239
and 303 nm (log ε 4.39 and 3.70); (ethanol–0.1 M NaOH, 1 : 1): λmax 267 (log ε 4.39). For
C H N O (196.1) calculated: 55.07% C, 6.16% H, 14.28% N; found: 54.78% C, 6.07% H,
9
12
2
3
1
4.07% N.
The mother liquors were applied onto a column of Dowex 50 (acid form; 20 ml). Elution with
water (200 ml), evaporation of the eluate and crystallization of the residue (200 mg, 30%) from water
afforded 153 mg (22%) of compound VIIb, m.p. 247 °C. UV spectrum (ethanol–0.1 M HCl, 1 : 1):
λmax 227 and 281 nm (log ε 4.04 and 4.09); (ethanol–0.1 M NaOH, 1 : 1): λmax 247 and 310 nm (log ε
4
4
.11 and 4.36). For C H N O (168.1) calculated: 49.98% C, 4.79% H, 16.66% N; found: 50.03% C,
7 8 2 3
.77% H, 16.58% N.
Washing the column with 5% aqueous ammonia (150 ml) and crystallization from ethanol gave
another 95 mg (12%) of compound VIb.
4
-(3-Butenyl)-5-ethoxycarbonylpyrimidin-2(1H)-one (VIc) and 5-(4-Pentenoyl)uracil (VIIc)
A mixture of compound Vd (720 mg, 3 mmol) and 0.1 M NaOH (60 ml, 6 mmol) was shaken at
room temperature for 30 min, neutralized with concentrated acetic acid and set aside at room tem-
perature overnight. The deposited product was filtered, washed with water and dried; yield 186 mg
(
2
28%) of compound VIc. The mother liquors were applied onto a column of Dowex 50 (acid form;
0 ml). The column was washed with water (250 ml) and the eluate was concentrated. The crystalline
residue (172 mg, 30%) was crystallized from water; m.p. 235 °C. UV spectrum (ethanol–0.1 M HCl,
1
3
: 1): λmax 227 and 282 nm (log ε 4.11 and 4.13); (ethanol–0.1 M NaOH, 1 : 1): λmax 249 and
11 nm (log ε 4.07 and 4.29). For C H N O (194.1) calculated: 55.64% C, 5.19% H, 14.42% N;
9
10
2
3
found: 55.57% C, 5.38% H, 14.69% N.
The column was then washed with 5% aqueous ammonia (200 ml) and the eluate was taken down.
Chromatography of the sirupy residue on a silica gel column (20 g) in ethyl acetate–acetone–ethanol–
water (40 : 2 : 2 : 1) afforded further amount (197 mg; 30%) of compound VIc. Crystallization of the
combined portions of compound VIc (383 mg) from ethyl acetate–light petroleum gave 233 mg
(
(
(
35%) of VIc, m.p. 106 – 108 °C. UV spectrum (ethanol–0.1 M HCl, 1 : 1): λmax 244 and 304 nm
log ε 4.28 and 3.70); (ethanol–0.1 M NaOH, 1 : 1): λmax 262 nm (log ε 4.41). For C H N O
222.1) calculated: 59.42% C, 6.35% H, 12.60% N; found: 59.35% C, 6.33% H, 12.48% N.
11
14
2
3
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

1
852
Ledvina, Farkas:
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Translated by M. Tichy.
Collect. Czech. Chem. Commun. (Vol. 59) (1994)