Some specific features of acid nitration of 2-substituted 4,6-dihydroxypyrimidines. Nucleophilic cleavage of the nitration products

Article abstract of DOI:10.1023/A:1012568305472

The nitration of 2-substituted 4,6-dihydroxypyrimidines in concentrated sulfuric acid yields the corresponding 5,5-dinitro derivatives. When the substituent in position 2 is an alkyl group, the nitration occurs both at position 5 and at the α-carbon atom of the side chain. Hydrolysis of 2-substituted 4,6-dihydroxy-5,5-dinitropyrimidines leads to formation of 1,1-diamino-2-R-2-nitroethylene derivatives. 1,1-Diamino-2,2-dinitroethylene was obtained by nitration of 4,6-dihydroxy-2-methylpyrimidine and subsequent hydrolysis of 4,6-dihydroxy-5,5-dinitro-2-(dinitromethylene)-2,5-dihydropyrimidine.

Full text of DOI:10.1023/A:1012568305472

Russian Journal of Organic Chemistry, Vol. 37, No. 5, 2001, pp. 729 733. Translated from Zhurnal Organicheskoi Khimii, Vol. 37, No. 5, 2001,
pp. 766 770.
Original Russian Text Copyright
2001 by Astrat’ev, Dashko, Mershin, Stepanov, Urazgil’deev.
Some Specific Features of Acid Nitration
of 2-Substituted 4,6-Dihydroxypyrimidines. Nucleophilic
Cleavage of the Nitration Products
A. A. Astrat’ev, D. V. Dashko, A. Yu. Mershin,
A. I. Stepanov, and N. A. Urazgil’deev
Tekhnolog Special Construction Technology Bureau, St. Petersburg State Institute of Technology,
Moskovskii pr. 26, St. Petersburg, 198013 Russia
fax: (812)3151159
Received May 15, 2000
Abstract The nitration of 2-substituted 4,6-dihydroxypyrimidines in concentrated sulfuric acid yields the
corresponding 5,5-dinitro derivatives. When the substituent in position 2 is an alkyl group, the nitration occurs
both at position 5 and at the -carbon atom of the side chain. Hydrolysis of 2-substituted 4,6-dihydroxy-5,5-
dinitropyrimidines leads to formation of 1,1-diamino-2-R-2-nitroethylene derivatives. 1,1-Diamino-2,2-dinitro-
ethylene was obtained by nitration of 4,6-dihydroxy-2-methylpyrimidine and subsequent hydrolysis of 4,6-di-
hydroxy-5,5-dinitro-2-(dinitromethylene)-2,5-dihydropyrimidine.
Acid nitration of heterocyclic compounds often
takes different pathways due to concomitant proto-
tropic transformations. The ambident character of
heterocycles also strongly affects the reaction course.
In particular, diazines, despite their sufficiently high
basicity, are fairly weak nucleophiles in electrophilic
substitution reactions. It is even more difficult to
interpret their reactivity when the molecule contains
a substituent capable of prototropic isomerization.
Unlike unsubstituted pyrimidine, its 4,6-dihydroxy
While studying the nitration of 2-substituted 4,6-di-
hydroxypyrimidines in concentrated sulfuric acid, we
have found that only the corresponding 5,5-dinitro
derivatives are formed. Unlike nitration in acetic acid
which provides relatively weak acidity of the medium,
the nitration in concentrated sulfuric acid does not
give 5-mononitropyrimidines. 5,5-Dinitro derivative
is the only reaction product even when the amount of
nitric acid is clearly insufficient. At the same time,
the nitration of 2-substituted 4,6-dihydroxypyrimi-
derivative is readily nitrated with nitric acid in acetic dines with aqueous nitric acid yields only mononitro
acid at 20 C, yielding 5-nitro-4,6-dihydroxypyrimi-
dine [1 6]. Under the same conditions 4,6-dihydroxy-
derivatives even with a large excess of HNO3.
In most cases, the formation of 5,5-dinitropyrimi-
dines was judged by the formation of geminal dinitro-
acetamide derivatives. By nitration of 2-amino-4,6-di-
hydroxypyrimidine in sulfuric acid and subsequent
treatment of the reaction mixture with water we
isolated N-diaminomethylene-2,2-dinitroacetamide (I)
whose structure was established on the basis of its
elemental composition and IR and 13C NMR spectra
2
-methylpyrimidine gives rise to 4,6-dihydroxy-2-
methyl-5-nitropyrimidine which is formed in high
yield [7] (Scheme 1). However, there are no published
data on nitration of such substrates in media with
high acidity and high nitrating power.
Scheme 1.
(
Scheme 2). The formation of nitroguanidine and
dinitromethane on treatment of I with concentrated
nitric acid provides an additional support to the pro-
posed structure.
Figure 1 shows the UV spectra of aqueous solu-
tions of compound I at different pH values. It is seen
that compound I is a weak acid (pKa 6.6); the
absorption of the conjugate anion is located in the
R = H, CH3.
_
___________
Deceased.
1
070-4280/01/3705-0729$25.00 2001 MAIK Nauka/Interperiodica

7
30
ASTRAT’EV et al.
Scheme 2.
Scheme 3.
region typical for most anions derived from geminal
dinitroalkanes [8] and , -dinitroacetamides [9].
Taking into account the results of nitration of
this intermediate was not studied, but it was firmly
established that its nitration leads to formation of
2
a double bond between C and the substituent. In the
1
2
-substituted 4,6-dihydroxypyrimidines in weakly and
H NMR spectrum of a solution of 4,6-dihydroxy-2-
strongly acidic media, we presumed that 5-mononitro
derivative formed in the first stage is low reactive;
therefore, it does not undergo further nitration. When
the acidity is high, 5-nitropyrimidine can undergo
protonation to give a reactive intermediate which is
nitrated to 5,5-dinitro derivative. The structure of
isopropylpyrimidine in concentrated sulfuric acid we
observed a doublet signal from the methyl group and
a septet from the CH proton, i.e., signals typical of
an isopropyl group. On addition to the solution of
nitric acid (as potassium nitrate) the doublet and
septet are converted into a singlet due to formation
of 5,5-dinitro derivative (Fig. 2). This means that the
nitration product has a quinoid structure (Scheme 3).
We failed to isolate 4,6-dihydroxy-2-isopropyli-
dene-5,5-dinitropyrimidine (II) from the reaction
mixture because of its high solubility in concentrated
sulfuric acid. Nevertheless, the amount of dinitro-
methane determined in the solution (after decomposi-
tion of the reaction mixture with water) indicated that
compound II was formed in 85% yield. The final
product of the nitration of 4,6-dihydroxy-2-methyl-
pyrimidine was 4,6-dihydroxy-5,5-dinitro-2-dinitro-
methylene-2,5-dihydropyrimidine (III) (Scheme 4).
The same product was also isolated from the reaction
mixture obtained by nitration of 4,6-dihydroxy-2-
methyl-5-nitropyrimidine.
Scheme 4.
Fig. 1. UV spectra of aqueous solutions of 1-diamino-
methyleneamino-2,2-dinitrovinyl alcohol (I). The numbers
on the curves denote the pH values.
R = H, NO2.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 5 2001

SOME SPECIFIC FEATURES OF ACID NITRATION
Compound III is unstable. It decomposed within
731
several hours, but we succeeded in proving its struc-
ture by elemental analysis and reactions with nucleo-
philes. The hydrolysis of III in water occurs instan-
taneously. The reaction on strong dilution (more than
5
00:1), pH 7, results in evolution of 1 mol of CO2.
An analogous reaction occurs in alkaline medium.
In this case 2-amino-1,1,5,5-tetranitro-4-oxo-3-aza-2-
pentene dipotassium salt (IV) is formed. Our attempt
to isolate the free tetranitro derivative by acidification
of a solution containing salt IV resulted in instanta-
neous hydrolysis with liberation of one more equiv-
alent of CO and 1 equiv. of dinitromethane and
2
formation of a light yellow solid which was assigned
the structure of 1,1-diamino-2,2-dinitroethylene (V)
(Scheme 5).
1
Fig. 2. Fragments of the H NMR spectra of a solution
of 4,6-dihydroxy-2-isopropylpyrimidine in concentrated
sulfuric acid (a) before and (b) after addition of potassium
nitrate.
Scheme 5.
Heating of compound III with anhydrous ethanol
or methanol gave the corresponding N-(1-amino-2,2-
dinitrovinyl)carbamate, 1 equiv of CO , and 1 equiv
2
of dinitromethane (Scheme 7).
Scheme 7.
The structure of compound V was determined from
1
3
its elemental composition and IR and C NMR spec-
tra. The 13C NMR spectrum of V contained only two
signals at
158.2 and 128.4 ppm. These data are
C
consistent with those reported for 1,1-bis(dimethyl-
amino)-2,2-dinitroethylene [10] which also showed
in the spectrum two carbon signals at
162.3 and
C
1
28.2 ppm. The formation of compound V with
R = Me (a), Et (b).
liberation of 2 equiv of CO and 1 equiv of dinitro-
2
methane was also observed on mixing pyrimidine III
with 5 7 parts of water (pH < 3) and on dilution with
water of the reaction mixture obtained in the nitration
of 4,6-dihydroxy-2-methylpyrimidine with a mixture
of sulfuric and nitric acids (Scheme 6). In such a way
we can obtain 1,1-diamino-2,2-dinitroethylene in
more than 80% yield by nitration of 4,6-dihydroxy-2-
methylpyrimidine withouth isolation of intermediate
tetranitro derivative III.
The formation of esters VIa and VIb indicates
that cleavage of 4,6-dihydroxy-5,5-dinitro-2-(dinitro-
methylene)-2,5-dihydropyrimidine begins with attack
4
by nucleophilic species on C of the pyrimidine ring.
It is interesting that 4,6-dihydroxy-2-methyl-5-
nitropyrimidine is readily nitrated to the correspond-
ing 5,5-dinitro derivative, whereas introduction of the
second nitro group into 4,6-dimethoxy-2-methyl-5-
nitropyrimidine is impossible. Our attempts to accom-
plish this transformation by varying the reaction
conditions (such as temperature, composition of the
nitrating mixture, and reaction time) were unsuccess-
ful. As a result, either the initial compound was
recovered from the reaction mixture or profound
decomposition products were isolated. In order to
elucidate the reason for the different reactivities of
Scheme 6.
4
,6-dihydroxy-2-methyl-5-nitropyrimidine and its
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 5 2001

7
4
32
ASTRAT’EV et al.
1
,6-dimethoxy analog, we examined the H NMR
The pKBH values were calculated as described in [13]
using the dependence of the ionization ratio logarithm
logI on the acidity function. The slopes of the linear
plots logI H for 4,6-dimethoxy-2-methyl-5-nitro-
+
spectra of these compounds in sulfuric acid solutions
with different concentrations. Judging by the position
of the methyl proton signal, the ionization of 4,6-di-
hydroxy-2-methyl-5-nitropyrimidine is well described
0
pyrimidine and logI H for 4,6-dihydroxy-2-methyl-
a
by the acidity function H corresponding to protona-
5-nitropyrimidine were 0.95 and 0.98, respectively.
a
tion of amides at the carbonyl oxygen atom [11]:
4
,6-Dihydroxy-2-methyl-5-nitropyrimidine.
pK
BH+
4.25. 4,6-Dimethoxy-2-methyl-5-nitropyrimi-
4,6-Dihydroxy-2-methylpyrimidine, 9 g (0.05 mol),
was added in portions to 21 ml of 98% HNO under
dine is a Hammett base with pK 2.2 (in terms
BH+
3
of H units) [12]. These values suggest different
0
vigorous stirring and cooling (15 20 C). The mixture
was stirred for 2 3 h at 15 20 C, cooled below 5 C,
and diluted with 30 ml of ice water. The mixture was
left to stand for 2 3 h, and the precipitate was filtered
off, washed with cold water, and dried in air. Yield
of the crude product 10 g. After recrystallization from
water, we obtained 9.1 g (75%) of the product with
mp 287 288 C (decomp.) [7].
mechanisms of protonation: 4,6-dimethoxy-2-methyl-
5
-nitropyrimidine is protonated at the ring nitrogen
atom, and its dihydroxy analog, at the exocyclic
oxygen atom (Scheme 8).
Scheme 8.
N-Diaminomethylene-2,2-dinitroacetamide (I).
-Amino-4,6-dihydroxypyrimidine, 12.6 g (0.07 mol),
2
was added in portions to 50 ml of concentrated sul-
furic acid, vigorously stirred at 15 20 C. To the
resulting mixture 22 g of 98% HNO was added,
3
maintaining the temperature at 15 20 C. After 1 h,
the mixture was poured into 700 800 ml of ice water
and was left to stand for 2 3 h. The precipitate was
filtered off, washed with water, and recrystallized
from 100 ml of aqueous DMF (1:4). Yield 9.4 g
1
Izomerization of the O-protonated form leads to
a reactive intermediate which readily undergoes
further nitration to 5,5-dinitro derivative. Presumably,
the rate of nitration of this intermediate is much
higher than the rate of nitration of the initial substrate.
Therefore, we observed no accumulation of 4,6-di-
hydroxy-2-methyl-5-nitropyrimidine in concentrated
sulfuric acid even when the amount of nitric acid was
insufficient. The failure to nitrate 4,6-dimethoxy-2-
methyl-5-nitropyrimidine in concentrated sulfuric acid
suggests that isomerization of its N-protonated form
does not give a reactive intermediate.
(50%). mp 167.5 C (decomp.). H NMR spectrum, ,
ppm: 8.1 s (NH2), 8.8 s (NH2). 13C NMR spectrum,
C, ppm: 156.83 [C(NO2)2], 156.09 (C O), 134.64
[C(NH2)2]. Found, %: C 18.69; H 1.47; N 36.48.
C3H3N5O5. Calculated, %: C 18.83; H 1.56; N 36.63.
4,6-Dihydroxy-5,5-dinitro-2-(dinitromethylene)-
2,5-dihydropyrimidine (III). 4,6-Dihydroxy-2-
methylpyrimidine, 12.6 g (0.07 mol), was added in
portions under vigorous stirring to 38 ml of concen-
trated sulfuric acid, maintaining the temperature at
15 20 C. The mixture was cooled to 5 10 C, and
85 g of 98% HNO was added. After 1 h, the mixture
3
was cooled to 0 5 C, and the precipitate was filtered
off, immediately washed with 20 ml of trifluoroacetic
anhydride and 20 ml of trifluoroacetic acid, and dried.
Yield 16.9 g (75%). The product had no definite
melting point. Found, %: C 19.58; H 0.03; N 27.38.
EXPERIMENTAL
1
13
The H and C NMR spectra were recorded on
1
a Bruker AC-300 spectrometer (300 MHz for H);
DMSO-d was used as solvent, and tetramethylsilane,
C H N O . Calculated, %: C 19.60; H 0.06; N 27.44.
5
2
6
10
6
as internal reference. The UV spectra were measured
on a Specord M40 spectrophotometer. The elemental
compositions were determined on a Hewlett Packard
2-Amino-1,1,5,5-tetranitro-4-oxo-3-aza-2-pentene
dipotassium salt (IV). Freshly prepared compound
III, 5 g (0.016 mol), was added with stirring at 15
20 C to a solution of 2 g (0.035 mol) of potassium
hydroxide in 15 ml of water. The solution was
evaporated in air, and the residue was recrystallized
from 10 ml of methanol. Yield 2.6 g (45%). mp 105 C
(decomp.). Found, %: C 13.50; H 0.78; N 23.46.
1
85B CHN-analyzer. The basicity of 4,6-dihydroxy-
-methyl-5-nitropyrimidine was determined by spec-
2
trophotometry at 320 nm ( B 7260,
BH+
6670 l
1
1
mol cm ); for 4,6-dimethoxy-2-methyl-5-nitropyri-
1
1
midine, 280 nm ( B 5980,
BH+
7200 l mol cm ).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 5 2001

SOME SPECIFIC FEATURES OF ACID NITRATION
733
C H K N O . Calculated, %: C 13.43; H 0.83; 61.37 (OCH ), 14.47 (CH ). Found, %: C 27.24;
4
2
2
6
9
2
3
N 23.50.
H 3.59; N 25.40. C H N O . Calculated, %: C 27.25;
5 8 4 6
H 3.63; N 25.4.
1
,1-Diamino-2,2-dinitroethylene (V). a. 4,6-Di-
hydroxy-2-methylpyrimidine, 12.6 g (0.07 mol), was
nitrated as described above for the synthesis of com-
pound III. The reaction mixture was cooled to 0 5 C
and poured into 600 700 ml of water. After 10 12 h,
the precipitate was filtered off and recrystallized from
DMF. Yield 8.1 g (75%). mp 220 C (decomp.).
REFERENCES
1
2
3
.
.
.
Segal, H. and Shapiro, D., J. Med. Pharm. Chem.,
959, vol. 1, pp. 371 380.
1
Nasyr, I.A., Mozgovaya, G.P., and Karabanov, Yu.V.,
Fiziol. Aktivn. Veshch., 1962, no. 14, p. 53.
1
13
H NMR spectrum, , ppm: 8.77 s (NH2). C NMR
spectrum, , ppm: 158.83 [C(NO ) ], 128.56
C(NH ) ]. Found, %: C 16.22; H 2.72; N 37.84.
Fel’dman, I.Kh. and Zlobina, V.I., Mechenye biolo-
gicheski aktivnye veshchestva (Labeled Biologically
Active Substances), Moscow: Atomizdat, 1962, p. 53.
C
2 2
[
2
2
C H N O . Calculated, %: C 16.11; H 2.62; N 37.68.
2
4
4
4
4
5
6
7
.
.
.
.
Davydenkov, P.R., Med. Promst. SSSR, 1962,
vol. 16, no. 1, p. 25.
b. Freshly prepared compound III, 10 g (0.03 mol),
was added at 15 20 C to 70 ml water under vigorous
stirring. If necessary, the mixture was acidified with
dilute sulfuric acid to pH 2 and was stirred for 1 2 h
at 18 20 C. The yellow crystalline product was fil-
tered off, washed with water, and dried in air. Yield
Boon, W.R., J. Chem. Soc., 1957, no. 5, pp. 2146
2
158.
US Patent no. 4434167, 1981; Ref. Zh., Khim.,
984, no. 23O135P.
1
Johnson, C.D., Katritzky, A.R., Kingsland, M.,
and Scriven, E.F.V., J. Chem. Soc. B, 1971, no. 1,
pp. 1 4.
4
.4 g (90%).
Methyl and ethyl N-(1-amino-2,2-dinitrovinyl)-
carbamates VIa and VIb. Freshly prepared com-
pound III, 10 g (0.03 mol), was added at 18 20 C to
8
9
.
.
Tselinskii, I.V., Kosmynina, V.N., Dronov, V.N.,
and Shokhor, I.N., Reakts. Sposobn. Org. Soedin.,
970, vol. 7, no. 1 (23), pp. 50 64.
50 ml of anhydrous methanol or ethanol. The mixture
1
was kept for 1 h at that temperature and was then
refluxed for 30 min. The solvent was removed under
reduced pressure (water-jet pump), and the residue
was recrystallized from aqueous DMF (1:4).
Krylov, V.K. and Tselinskii, I.V., Reakts. Sposobn.
Org. Soedin., 1972, vol. 9, no. 3 (33), pp. 729 744.
1
0. Baum, K., Begelow, S.S., Nguyen, N.V., Archi-
bald, T.G., Gilardi, R., Flippen-Anderson, J.L., and
George, C., J. Org. Chem., 1992, vol. 57, no. 1,
pp. 235 241.
Ester VIa. Yield 3.4 g (45%). mp 151 C (decomp.).
1
H NMR spectrum, , ppm: 8.77 s (NH ), 3.8 s (CH ).
2
3
1
3
C NMR spectrum,
, ppm: 159.77 [C(NO2)2],
C
11. Yates, K., Stevens, J.B., and Katritzky, A.R.,
1
56.73 (C O), 144.5 (NHCNH ), 51.37 (OCH ).
2
3
J. Chem. Soc., 1964, vol. 42, no. 8, pp. 1957 1970.
Found, %: C 23.3; H 3.01; N 27.2. C H N O . Cal-
4
6
4
6
1
1
2. Vinnik, M.O., Usp. Khim., 1966, vol. 35, no. 1,
culated, %: C 23.28; H 2.91; N 27.14.
pp. 1922 1952.
Ester VIb. Yield 3.2 g (45%). mp 141 C (decomp.).
3. Bershtein, I.Ya. and Kaminskii, Yu.L., Spektrofoto-
metricheskii analiz v organicheskoi khimii (Spectro-
photometric Analysis in Organic Chemistry), Lenin-
grad: Khimiya, 1975, pp. 149 152.
1
H NMR spectrum, , ppm: 8.77 s (NH ), 3.9 q
2
1
3
(
CH ), 1.9 t (CH ). C NMR spectrum, C, ppm:
2 3
1
59.73 [C(NO ) ], 155.56 (C O), 144.5 (NHCNH ),
2 2 2
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 5 2001