SYNTHESIS OF SOME m-SUBSTITUTED 1-PHENYL-6-AZAURACILS

Full text of DOI:10.1135/cccc19942741

New Compounds
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SYNTHESIS OF SOME m-SUBSTITUTED 1-PHENYL-6-AZAURACILS*
Jan SLOUKA, Vojtech BEKAREK and Jan HLAVAC
Department of Analytical and Organic Chemistry,
Palacky University, 771 46 Olomouc, The Czech Republic
Received August 30, 1994
Accepted September 7, 1994
Dedicated to Professor Milan Kratochvil on the occasion of his 70th birthday.
In spite of the fact that anticoccidal effects of many 1-aryl-6-azauracils are known over
20 years1, searching of the more effective compounds in this group is still continuing2,3.
The revival of interest in these compounds have come also with connection of finding
out their herbicidal effects4.
Many 1-aryl-6-azauracils derivatives were prepared so far, among them the repre-
sentation of m-substituted 1-phenyl derivatives is relatively poor. In this communica-
tion we report on the synthesis of the starting material – dicarbamate I, which was used
for the preparation of some new 1-phenyl-6-azauracil derivatives II, containing simple
nitrogeneous group in m-position. We focused also on the compounds III having two
6-azauracil rings mutually bonded in m-position to the benzene ring. These compounds
can form hydrogen bonds simultaneously with two bonding centres of fitted substrate
and so they can serve as model compounds for the interaction studies. From this type
of compounds the dinitrile IIIa is known so far5.
By diazoniation of ethyl 3-aminophenylcarbamate6 and subsequent coupling with
ethyl cyanoacetylcarbamate the dicarbamate I was prepared in good yield. As it exists
as (Z)-isomer stabilized by intramolecular hydrogen bond7, it easily cyclizes to
1-(3-ethoxycarbonylaminophenyl)-6-azauracil-5-carbonitrile (IIa). This nitrile, as
well as nitriles IIb, IIc (ref.5) served as starting materials for preparation of all other
compounds. Thus, by addition of hydrogen sulfide, the nitriles IIa and IIc were con-
verted to corresponding thioamides IIe and IId, respectively. Thioamide IId was more
advantageously obtained directly from nitrile IIb, because by the reaction with am-
monium sulfide simultaneously proceeds the reduction of the nitro group. 1-(3-Amino-
* Part XXXVIII in the series On 1-Aryl-6-azauracils; Part XXXVII: Acta Univ. Palacki. Olomuc., Fac.
Rerum Nat. 108, 89 (1992).
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phenyl)-6-azauracil-5-carboxylic acid (IIg) was obtained easily by acidic hydrolysis of
nitriles IIa, IIc as well as thioamides IId and IIe and also by reduction of the nitro acid
IIf, which was obtained by acidic hydrolysis of nitrile IIb. By diazoniation of amino
acid IIg with subsequent coupling with ethyl cyanoacetylcarbamate ethyl 3-(5-cyano-6-
azauracil-1-yl)phenylhydrazonocyanoacetylcarbamate (IIh) was prepared, which was
cyclized to 1-[3-(5-cyano-6-azauracil-1-yl)phenyl]-6-azauracil-5-carboxylic acid (IIIb).
This acid was hydrolyzed to form dicarboxylic acid IIIc, which was obtained also by
hydrolysis of dinitrile IIIa. The acid IIIc was converted by thermic decarboxylation to
1,1′-(m-phenylen)-bis-6-azauracil (IIId). By addition of hydroxylamine to dinitrile IIIa
the corresponding diamidoxim IIIe was obtained. Through boiling with acetic anhydride
this compound gave 1,3-bis[5-(5-methyl-1,2,4-oxadiazol-3-yl)-6-azauracil-1-yl]benzene
IIIf. The starting dinitrile IIIa was obtained according to the described procedure8.
EXPERIMENTAL
The melting points were determined by means of a Boetius apparatus and they are not corrected. The
IR spectra (cm−1) were measured with an IR-75 apparatus (Zeiss) using the KBr disc technique.
Ethyl (Z)-3-(Ethoxycarbonylaminophenyl)hydrazonocyanoacetylcarbamate (I)
A solution of ethyl m-aminophenylcarbamate hydrochloride6 (2.20 g, 10.2 mmol) in a mixture of
water (55ml) and 37% HCl (5 ml) was cooled in an ice bath and the solution of NaNO2 (690 mg,
10.0 mmol) in ice water (8 ml) was added with stirring. The solution was left to stand in ice bath
with intermittent stirring for 65 min, whereupon it was added portionwise to a stirred mixture ob-
tained by dissolving ethyl cyanoacetylcarbamate (2.10 g, 13.45 mmol) in warm water (500 ml), cooling
in ice bath, adding CH3COONa (35 g) and crushed ice. The reaction mixture was left at 0 – 5 °C
with stirring 24 h. The formed yellow solid was then collected by suction, washed with water and
dried in air. Yield 3.34 g (96%) of the compound I, m.p. 193 – 195 °C (ethanol). For C15H17N5O5
(347.3) calculated: 51.87% C, 4.93% H, 20.17% N; found: 51.91% C, 4.86% H, 20.15% N. IR spec-
trum: 1 690, 1 703, 1 762 (CO), 2 212 (CN).
2-(3-Ethoxycarbonylaminophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (IIa)
Method A. A mixture of the dicarbamate I (1.05 g, 3.02 mmol), Na2CO3 (1.05 g) and water (50 ml)
was heated on boiling water bath until a solution was formed and then for another 20 min. After
addition of a small amount of charcoal the reaction mixture was filtered and acidified by acetic acid
to pH 3.5. The next day the formed crystalline solid was collected by suction, washed with water and
dried. Yield of the compound IIa was 738 mg (81%), m.p. 221 – 223 °C (ethanol–water). For
C13H11N5O4 (301.3) calculated: 51.83% C, 3.68% H, 23.25% N; found: 51.55% C, 3.67% H, 23.36% N.
IR spectrum: 1 676, 1 685, 1 710, 1 740 (CO), 2 230 (CN).
Method B. A mixture of the compound I (700 mg, 2.02 mmol) and xylene (60ml) was refluxed for
50 h, concentrated to ca 15 ml and cooled. The formed crystalline solid was collected by suction,
washed with benzene and dried. Yield 583 mg (96%) of the compound IIa, m.p. 221 – 223°C (etha-
nol–water).
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2-(3-Aminophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazin-6-carbothioamide (IId)
A solution of IIb (ref.5, 500 mg, 1.93 mmol) in 5% aqueous ammonia (20 ml) was saturated for 50 min
with hydrogen sulfide, allowed to stand in a stoppered flask at room temperature for 6 days and then
evaporated to dryness on the boiling water bath. The residue was treated with 5% aqueous ammonia
(30 ml) and after several hours the mixture was filtered and sulfur on filter was repeatedly washed
with 2% aqueous ammonia. Combined filtrates were evaporated, the residue was treated with water
(3 ml) and acidified with acetic acid to pH 5. After several hours the crystalline solid was collected
by suction, washed with water and dried on air. The yield of the compound IId monohydrate was 411 mg
(76%), m.p. (dec.) 272 – 275 °C (ethanol–water). For C10H11N5O3S (281.2) calculated: 42.71% C,
3.94% H, 24.90% N; found: 42.98% C, 3.86% H, 24.71% N. IR spectrum: 1 596 (CO).
2-(3-Ethoxycarbonylaminophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazin-6-carbothioamide (IIe)
A solution of the compound IIa (305 mg, 1.01 mmol), water (9 ml) and 25% aqueous ammonia (0.5 ml)
was saturated with hydrogen sulfide, the mixture was left to stand 4 days in a stoppered flask and
then acidified with acetic acid. The next day the formed crystalline solid was collected by suction,
washed with water and dried in air. Yield of the compound IIe dihydrate was 314 mg (84%), m.p.
206 – 208 °C (ethanol–water). For C13H17N5O6S (371.3) calculated: 42.05% C, 5.50% H, 18.86% N;
found: 41.81% C, 5.20% H, 18.57% N. IR spectrum: 1 600, 1 710, 1 740 (CO).
2-(3-Nitrophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazin-6-carboxylic Acid (IIf)
A mixture of the nitrile5 IIb (1.10 g, 4.24 mmol), 37% HCl (32 ml) and water (25 ml) was refluxed
for 3 h and cooled. The next day the separated crystalline solid was collected by suction, washed
with water and dried in air. The yield of the compound IIf monohydrate was 1.035 g (82%). Above
the temperature 110 °C the compound looses crystalline water and then melts at 191 – 193 °C. For
C10H8N4O7 (296.2) calculated: 40.55% C, 2.72% H, 18.92% N; found: 40.47% C, 2.77% H, 18.89% N.
IR spectrum: 1 610, 1 710 (CO); 1 350, 1 536 (NO2).
2-(3-Aminophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic Acid (IIg)
Method A: A mixture of IIa (500 mg, 1.66 mmol), 37% HCl (60 ml) and water (75 ml) was re-
fluxed 5 h and then evaporated to dryness. The residue was treated with water (5 ml) and (NH4)2CO3
(75 mg) and the next day crystalline solid was collected by suction, washed with little amount of
water and dried in air. The yield of the IIg monohydrate was 312.5 mg (71%), m.p. (dec.) 186 – 188 °C
(water). The hydrolysis of thioamide IIe occurs by the same procedure and the hydrolysis of nitrile
IIc (ref.5) with shorter reaction time (3 h) proceeds as well. For C10H10N4O5 (266.2) calculated:
45.11% C, 3.79% H, 21.05% N; found: 44.98% C, 3.95% H, 20.90% N. IR spectrum: 1 595, 1 612,
1 690, 1 725 (CO).
Method B: A solution of IIf (700 mg, 2.36 mmol) in mixture of 25% aqueous ammonia (7 ml) and
water (15 ml) was 40 min saturated with hydrogen sulfide. The mixture was left to stand 4 days in
stoppered flask and then evaporated on boiling water bath. The residue was treated with mixture of
37% HCl (1 ml) and water (20 ml). Reaction mixture was warmed to about 60 °C, filtered, sulfur on
filter was washed with warm water and combined filtrates were evaporated to dryness. The residue
was treated with water (4 ml) and pH was adjusted to 3 – 4 by addition of CH3COONa. The next
day crystalline solid was collected by suction, washed with water and dried on air. The yield of IIg
monohydrate was 587 mg (93%), m.p. (dec.) 186 – 188 °C (water).
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Ethyl (Z)-(3,5-Dioxo-6-carboxy-2,3,4,5-tetrahydro-1,2,4-triazin-2-yl)phenylhydrazono-
cyanoacetylcarbamate (IIh)
A solution of IIg . H2O (545 mg, 2.05 mmol) in mixture of 37% HCl (1.8 ml) and water (16 ml) was
cooled in ice bath and diazotized with a solution of NaNO2 (138 mg, 2.00 mmol) in ice water (4 ml).
The solution was left to stand in ice bath with stirring 35 min and then it was added portionwise to
a stirred mixture obtained by dissolving ethyl cyanoacetylcarbamate (430 mg, 2.75 mmol) in warm
water (85 ml), adding CH3COONa (4.0 g) and cooling in ice bath. The reaction mixture was left to
stand at 0 – 5 °C with occasional stirring 24 h, acidified to pH 1 and yellow solid was then collected
by suction, washed with water, and dried on air. Yield of IIh monohydrate was 764 mg (88%),
m.p. 263 – 265 °C (ethanol–water). For C16H15N7O7 (433.4) calculated: 44.35% C, 3.49% H, 22.63%
N; found: 44.08% C, 3.52% H, 22.35% N. IR spectrum: 1 610, 1 690, 1 766 (CO), 2 213 (CN).
1,3-Bis(3,5-dioxo-6-cyano-2,3,4,5-tetrahydro-1,2,4-triazin-2-yl)benzene (IIIa)
A mixture of ethyl (3,5-dioxo-6-cyano-2,3,4,5-tetrahydro-1,2,4-triazine-2-yl)phenylhydrazono-
cyanoacetylcarbamate5 (200 mg, 0.505 mmol) and pyridine (15 ml) was refluxed for 24 h and then
evaporated to dryness. The residue was treated with water (3 ml) and acidified with 37% HCl to pH 1.
After several hours the crystalline solid was collected by suction, washed with water and dried in air.
Yield of the IIIa monohydrate was 163 mg (88%), after recrystallization from water, m.p. and IR
spectrum were identical with the data of this compound prepared before5.
2-[3-(3,5-Dioxo-6-cyano-2,3,4,5-tetrahydro-1,2,4-triazin-2-yl)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-
1,2,4-triazin-6-carboxylic acid (IIIb)
A mixture of IIh . H2O (440 mg, 1.02 mmol), Na2CO3 (600 mg) and water (20 ml) was heated on
boiling water bath for 25 min. After addition of charcoal the reaction mixture was filtered, concen-
trated to about 5 ml and acidified to pH 1. After several hours the crystalline solid was collected by
suction, washed with water and dried on air. The yield of IIIb monohydrate was 318 mg (81%), m.p.
272 – 274 °C (water). For C14H9N7O7 (387.3) calculated: 43.42% C, 2.34% H, 25.32% N; found:
43.20% C, 2.26% H, 25.22% N. IR spectrum: 1 600, 1 700 (CO), 2 238 (CN). By drying of the
monohydrate at 120 °C it was found the weight decrease corresponding to loss of one molecule of
water.
1,3-Bis(3,5-dioxo-6-carboxy-2,3,4,5-tetrahydro-1,2,4-triazin-2-yl)benzene (IIIc)
A mixture of IIIb . H2O (200 mg, 0.52 mmol), 37% HCl (20 ml) and water (20 ml) was refluxed for
3 h and cooled. The next day was the solid collected by suction, washed with water and dried on air.
The yield of IIIc dihydrate was 193 mg (88%), m.p. (dec.) 252 – 254 °C (water). For C14H12N6O10
(424.3) calculated: 39.63% C, 2.85% H, 19.81% N; found: 39.60% C, 2.71% H, 19.74% N. IR spec-
trum: 1 700, 1 730 (CO). The same procedure was used for preparation of the compound IIIc from
the dinitrile IIIa.
1,3-Bis(3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazin-2-yl)benzene (IIId)
The acid IIIc . 2 H2O (110 mg, 0.26 mmol) was heated at 240 – 260 °C until decarboxylation had
ceased. The residue was recrystallized from water with use of charcoal and the filtrate was concen-
trated to a small volume. The next day the crystalline solid was collected by suction, washed with
water and dried on air. Yield of IIId dihydrate was 71 mg (82%), m.p. 163 – 165 °C. For
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Slouka, Bekarek, Hlavac:
C12H12N6O6 (336.3) calculated: 42.86% C, 3.60% H, 24.99% N; found: 42.61% C, 3.35% H, 24.72% N.
IR spectrum: 1 707 (CO).
1,3-Bis[3,5-dioxo-6-(N-hydroxyamidino)-2,3,4,5-tetrahydro-1,2,4-triazin-2-yl]benzene (IIIe)
To a solution of the nitrile5 IIIa . H2O (190 mg, 0.52 mmol) in 8% aqueous ammonia (15 ml) was
added hydroxylamine hydrochloride (280 mg) and the solution was allowed to stand in stoppered
flask at room temperature for 10 days. After evaporating under reduced pressure the residue was
mixed with a small volume of water and several drops of acetic acid. Next day the crystals were
collected by suction, washed with water and air-dried at room temperature. The yield of IIIe dihy-
drate was 177 mg (76%). The compound decomposed above 300 °C and did not melt up to 350 °C.
For C14H16N10O8 (452.4) calculated: 37.17% C, 3.56% H, 30.97% N; found: 37.47% C, 3.40% H,
30.95% N. IR spectrum: 1 705 (CO).
1,3-Bis[3,5-dioxo-6-(5-methyl-1,2,4-oxadiazol-3-yl)-2,3,4,5-tetrahydro-1,2,4-triazin-2-yl]benzene (IIIf)
To a boiling solution of IIIe . 2 H2O (120 mg, 0.27 mmol) in acetic acid (7 ml) was added acetan-
hydride (20 ml) and reaction mixture was refluxed 4 h and then treated with water (20 ml). The next
day after addition of a small amount of charcoal the solution was filtered and evaporated to dryness.
The residue was mixed with water (3 ml) and the crystals were after several hours collected by suc-
tion and dried at 140 °C. Yield 94 mg of the compound IIIf (76%), m.p. 343 – 345 °C (water). For
C18H12N10O6 (464.4) calculated: 46.56% C, 2.61% H, 30.23% N; found: 46.41% C, 2.73% H,
30.04% N. IR spectrum: 1 703 (CO).
REFERENCES
1. Pfizer Ch. and Co., Inc.: Brit. 1 206 698; Chem. Abstr. 74, 53856 (1971).
2. Fukami H., Hashimoto M., Niwata S., Imose S., Kanaguchi H., Takahashi H., Takahashi T.: Eur.
Pat. Appl. EP 576 251; Chem. Abstr. 120, 270461 (1994).
3. Cooper Ch. B., Mc Farland J. W., Blair K. T., Foutaine E. H., Jones Ch. S., Muzz M. L.: Bioorg.
Med. Chem. Lett. 4, 835 (1994).
4. Lyga J. W., Halling B. P., Witkowski D. A., Patera R. M., Seeley J. A., Plummer M. J., Hotzman
F. W. in: Synthesis and Chemistry of Agrochemicals II (D. R. Baker, J. G. Fenyes and W. K.
Moberg, Eds), ACS Symposium Series 443, p. 170. ACS, Washington D.C. 1991.
5. Slouka J.: Collect. Czech. Chem. Commun. 55, 2967 (1990).
6. Slouka J., Nalepa K.: Z. Chem. 26, 134 (1986).
7. Bekarek V., Slouka J.: Collect. Czech. Chem. Commun. 39, 566 (1974).
8. Slouka J. : Monatsh. Chem. 99, 1808 (1968).
Translated by autor (J. H.).
Errata:
Slouka J.: Collect. Czech. Chem. Commun. 55, 2967 (1990)
p. 2973, line 31:
For “and” read “, 160 ml water and”.
Collect. Czech. Chem. Commun. (Vol. 59) (1994)