Conversion of amino group in position 6 of uracil

Article abstract of DOI:10.1023/B:COHC.0000028633.76885.60

The possibility of substituting amino groups in position 6 of 5-R-uracils (R = H, NO) by hydroxylamine and phenylhydrazine has been demonstrated. The products of substitution - 6-hydroxyaminouracil, 5,6-dihydroxydiiminouracil, and 5-nitroso-6-phenylhydraz

Full text of DOI:10.1023/B:COHC.0000028633.76885.60

Chemistry of Heterocyclic Compounds, Vol. 40, No. 3, 2004
CONVERSION OF AMINO GROUP
IN POSITION 6 OF URACIL
A. A. Yavolovskii and E. I. Ivanov
The possibility of substituting amino groups in position 6 of 5-R-uracils (R = H, NO) by hydroxylamine
and phenylhydrazine has been demonstrated. The products of substitution – 6-hydroxyaminouracil,
5,6-dihydroxydiiminouracil, and 5-nitroso-6-phenylhydrazinouracil – are readily oxidized into
1,2,5-oxadiazolo- and 1,2,3-triazolo[3,4-d]pyrimidine N-oxides respectively.
Keywords: 5,6-dihydroxydiiminouracil, 6-hydroxyaminouracil, 5-nitroso-6-phenylhydrazinouracil,
1,2,5-oxadiazolo- and 1,2,3-triazolo[3,4-d]pyrimidine N-oxides, nucleophilic substitution, oxidation.
The most widely used method for the preparation of pyrimidines with nitrogen-containing functional groups
in positions 2,4 (or 6) is the nucleophilic substitution on chloropyrimidines [1-3]. Transamination [4, 5] has received
considerably less attention although in some cases aminopyrimidines are much more available than the corresponding
4(6)-chloro derivatives.
O
HN
O
N
H
2
NHOH
+
NH3OH
R = H
O
O
N
O
O
R
+
HN
NOH
NOH
NH3OH
R = NO
HN
HN
[O]
O
O
N
H
1a,b
NH2
R
N
O
N
H
O
N
H
4
+
3
NHNH3
R = NO
O
N
O
O
NO
HN
O
HN
[O]
R
N
N
N
H
6a,b
O
N
H
NH
NH
R
5a,b
1 a R = H, b R = NO; 5 a R = H, b R = t-Bu; 6 a R = H, b R = t-Bu
__________________________________________________________________________________________
A. V. Bogatsky Physico-Chemical Institute, Ukraine National Academy of Sciences, Odessa 65080,
Ukraine; e-mail: ivanov.u@paco.net. Translated from Khimiya Geterotsiklicheskikh Soedinenii, pp. 443-446,
March, 2004. Original article submitted July 27, 2001.
0009-3122/04/4003-0361©2004 Plenum Publishing Corporation
361

TABLE 1 . Spectral Characteristics of the Compounds Synthesized
Com-
pound
Mass spectrum, m/z (Irel, %)
IR spectrum, ν, cm-1
2
143(83), 100(100), 68(12), 58(39), 57(14)
3400, 3230-3000, 1730, 1710, 1680,
1660
3
154(39), 111(12), 70(10), 68(15), 58(8), 54(10),
53(13), 43(100)
3320-3000, 1720, 1680, 1600
4
170(100), 154(10), 140(76), 97(10), 70(15),
69(31), 68(7), 67(59), 54(22), 53(14)
3510, 3480, 3300-3000, 1750, 1700,
1680, 1660, 1590, 1540, 1520
5a
247(20), 245(8), 231(18), 229(33), 213(8),
3250-3000, 1710, 1700, 1680, 1660,
202(8), 200(6), 186(18), 105(24), 92(13), 91(14), 1645, 1590, 1570, 1550, 1530
77(100)
5b
303(15), 301(8), 287(59), 285(25), 272(45),
270(95), 149(61), 132(71), 133(100), 119(53),
117(31), 110(30), 105(35), 103(15), 93(20),
91(78), 77(41)
3250-3000, 1730, 1720, 1700, 1690,
1670, 1650, 1600, 1570, 1630, 1510,
15000
6а
245(28), 229(4), 139(9), 105(27), 96(6),
77(100), 51(19)
3200-3000, 1720, 1705, 1695, 1690,
1670, 1600, 1560
6b
301(51), 285(12), 270(35), 230(5), 222(6),
207(11), 161(13), 133(100), 117(16), 105(25),
91(37), 77(21)
3240-3000, 1715, 1680, 1590, 1560
We have established that 6-aminouracil (1a) and its 5-nitroso derivative (1b) readily undergo acid
catalyzed substitutions with hydroxylamine and phenylhydrazine. Use of the free bases or their salts with weak
acids does not always lead to the satisfactory results which were achieved by using a mixture of acetate and
hydrochloride salts as the nucleophile. We obtained 6-hydroxyaminouracil (2) by refluxing 6-aminouracil (1a)
[6,7] for a short time with an excess of a mixture of hydroxylaminium acetate and chloride in water. Substitution
of the amino group in 6-amino-5-nitrosouracil 1b by hydroxylamine at 65-75°C was completed in 1.5-2 h to give
5,6-dihydroxydiiminopyrimidin-2,4-dione (3). Dioxime 3 is a colorless compound, which dissolves poorly in
organic solvents and water, but well in aqueous solutions of amines and alkalis.
The molecular ion is absent from the mass spectrum of oxime 3. The heaviest ion in the mass spectrum
of 3 corresponds to the loss of water from the molecular ion [M - 18]+. Dioxime 3 is converted to
1,2,5-oxadiazolo[3,4-d]pyrimidin-5(4H),7(6H)-dione (4) by oxidation with concentrated nitric acid. The
accessibility of the starting materials and the high yields of this synthesis for furoxanopyrimidine 4 is more
effective than methods published previously [8-10]. It should be noted that the dioximes are not formed on
nitrosation of 1-R-6-hydroxyamino-3-methyluracils [8,9] but instead the products of oxidative cyclization,
furoxanopyrimidines, the mass spectra of which contain intense peaks at [M + 2]+. The authors attributed the
presence of these peaks to the addition of two hydrogen atoms as a result of adsorption of water under the
spectrometric conditions. In our case the intensity of the [M + 2]+ peaks corresponded to the isotopic
composition of 4 which is apparently connected with the low stability of the hydrogenated form 3. In reaction
conditions similar to those with hydroxylamine, the substitution of the amino group in 1b by phenylhydrazine
gave 5-nitrosophenylhydrazones 5a and 5b. Subsequent oxidation under mild conditions with K3[Fe(CN)6] in
alkaline media gave the 1,2,3-triazolopyrimidine N-oxides 6a and 6b. Although the N-oxides 6a and 6b
appeared to be stable with respect to 30% hydrogen peroxide, use of H2O2 to oxidize the nitrosohydrazines 5a
and 5b was accompanied by side reactions and consequently gave impure 6a and 6b as final products.
EXPERIMENTAL
Purity of compounds was monitored by TLC on Silufol UV-254 strips. Mass spectra were recorded on a
Varian MAT-112 with an ionizing voltage of 70 eV and a chamber temperature of 220°C. IR spectra of nujol mulls
were recorded with Specord-80 instrument
362

6-Hydroxyaminopyrimidin-2,4-(1H,3H)-dione (2). A mixture of 6-aminouracil 1a (1.0 g, 8 mmol),
hydroxylamine hydrochloride (2 g, 30 mmol), and sodium acetate (1.6 g, 20 mmol) was boiled in water (75 ml)
until it dissolved. The mixture was slowly evaporated under normal conditions until crystallization began. The
precipitate was separated and recrystallized from water. Yield 0.9 g (80%); mp 320°C (dec.). Found, %: C 33.62;
H 3.48; N 29.11. C4 H5N3O3. Calculated, %: C 33.57; H 3.50; N 29.37.
5,6-Dihydroxydiiminopyridin-2,4-(1H,3H)-dione (3). A mixture of 6-amino-5-nitrosouracil (1.4 g,
9 mmol), hydroxylamine hydrochloride (2 g, 30 mmol), and sodium acetate (1.6 g, 20 mmol) in water (50 ml)
was heated to 65-70°C with intense stirring to give a colorless solution. The precipitate was filtered off, washed
with cold water, and dried in the air. Yield 1.4 g (91%); mp >250°C. Found, %: C 30.12; H 2.36; N 32.40.
C4H4N4O4. Calculated, %: C 27.90; H 2.33; N 32.56.
1,2,5-Oxadiazolo[3,4-d]pyrimidin-5,7-(4H,6H)dione N-Oxide (4). A solution of compound 3 (1.7 g,
100 mmol) in nitric acid (10 ml) and sulfuric acid (1 ml) was cautiously heated at 40-50°C until solution
occurred. The reaction mixture was cooled diluted with twice as much water, and neutralized with cold ammonia
solution. The precipitate was filtered off, washed with water, and dried in a desiccators over P2O5. Yield 1.48 g
(87%); mp 260°C. Found, %: C 28.12; H 1.22; N 32.99. C4H2N4O4. Calculated, %: C 28.24; H 1.18; N 32.94.
6-[2-(4-R-Phenylhydrazino)pyrimidin-2,4-(1H,3H)-diones, (5a,b).
A
mixture of 6-amino-5-
nitrosouracil 1b , phenylhydrazine hydrochloride (20 mmol), and sodium acetate (15 mmol) in water (150 ml)
was heated for 2 h at 70°C with intense stirring. The precipitate was filtered off, washed twice with hot water ,
dried in the air, and washed with toluene until the washing were no longer colored. It was dried in air again to
give a yield of 1.98 g (80%) of chromatographically pure 5a; mp 250°C. Found, %: C 48.50; H 3.66; N 28.37.
C10H9N5O3. Calculated, %: C 48.58; H 3.64; N 28.34. Yield of compound 5b, 2.33 g (77%); mp 232-238°C.
Found, %: C 55.43; H 5.63; N 23.09. C14H17N5O3. Calculated, %: C 55.45; H 5.61; N 23.10.
1-Oxides of 2-(4-R-Phenyl)-1,2,3-triazolo[4,5-d]pyrimidin-5,7-(4H,6H)diones (6a,b). Compound 5a
(10 mmol) and small portions of a saturated aqueous solution of sodium hydroxide (60 mmol) were added with
stirring to a solution of K3[Fe(CN)6] (60 mmol) in water (100 ml). Stirring was continued until the color of the
initial solution had disappeared. The solution was then neutralized with acetic acid. The precipitate was filtered
off, washed with water, and recrystallized from ethanol to give compound 6a (1.84 g, 75%); mp >300°C.
Found, %: C 48.95; H 2.8; N 28.56. C10H7N5O. Calculated, %: C 48.98; H 2.86; N 28.57. Yield of compound
6b, 1.8 g (60%); mp 250-255°C. Found, %: C 55.80; H 4.95; N 23.27. C14H15N3O3. Calculated, % : C 55.81;
H 4.98; N 23.25.
REFERENCES
1.
2.
3.
4.
5.
A. V. Ivashenko and O. N. Garicheva, Khim. Geterotsikl. Soedin., 579 (1982).
W. Pfleiderer and K. H. Schundehutte, Liebig Ann. Chem., 612, 158 (1958).
F. Yoneda and T. Nagamatsu, Synthesis, 177 (1975).
G. W. Whitehead and J. J. Traverso, J. Am. Chem. Soc., 82, 3971 (1960).
H. Sun, Ch. Zhi, G. E. Wright, D. Ubiali, M. Pregnolato, A. Verri, F. Focher, and S. Spadari, J. Med.
Chem., 42, 2344 (1999).
6.
7.
W. Traube, Ber., 3035 (1900).
K. Burger, Talanta, 8, 77 (1961).
8.
9.
10.
F. Yoneda, Y. Sakuma, and M. Ueno, J. Heterocycl. Chem., 10, 415 (1973).
F. Yoneda, and Y. Sakuma, J. Heterocycl. Chem., 10, 993 (1973).
C. Temple, C. L. Kussner, and J. A. Montgomery, J. Org. Chem., 10, 2086 (1967).
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