Nitro derivatives of pyrrolo[3,2-d]pyrimidine-2,4-diones: Synthesis of amines and new polynuclear heterocycles based thereon

Article abstract of DOI:10.1134/S1070428017100128

The nitration of 1,3-dimethylpyrrolo[3,2-d]pyrimidine-2,4-diones under different conditions led to the formation of their 6(7)-mono- and 6,7-dinitro derivatives which were reduced to the corresponding amines. The latter reacted with α- and β-dicarbonyl compounds, as well as with ortho-quinones to give a number of new polycyclic heteroaromatic systems.

Full text of DOI:10.1134/S1070428017100128

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2017, Vol. 53, No. 10, pp. 1564–1572. © Pleiades Publishing, Ltd., 2017.
Original Russian Text © Yu.N. Tkachenko, L.D. Popov, A.F. Pozharskii, S.A. Borodkin, S.I. Levchenkov, 2017, published in Zhurnal Organicheskoi Khimii,
2017, Vol. 53, No. 10, pp. 1536–1543.
Nitro Derivatives of Pyrrolo[3,2-d]pyrimidine-2,4-diones:
Synthesis of Amines and New Polynuclear Heterocycles
Based Thereon
Yu. N. Tkachenkoa, L. D. Popova,* A. F. Pozharskiia,
S. A. Borodkina, and S. I. Levchenkova, b
a Southern Federal University, ul. Zorge 7, Rostov-on-Don, 344090 Russia
*e-mail: ldpopov@mail.ru
b Southern Scientific Center, Russian Academy of Sciences, ul. Chekhova 41, Rostov-on-Don, 344006 Russia
Received April 21, 2017
Abstract—The nitration of 1,3-dimethylpyrrolo[3,2-d]pyrimidine-2,4-diones under different conditions led to
the formation of their 6(7)-mono- and 6,7-dinitro derivatives which were reduced to the corresponding amines.
The latter reacted with α- and β-dicarbonyl compounds, as well as with ortho-quinones to give a number of
new polycyclic heteroaromatic systems.
DOI: 10.1134/S1070428017100128
Pyrrolo[3,2-d]pyrimidine-2,4-diones and their
derivatives are structurally related to such important
natural compounds as uracils, xanthines, and indoles.
All these compounds are referred to as privileged
pharmacophores that are widely used in the design and
preparation of new medicines [1–3]. Therefore, de-
velopment of new methods for the synthesis and mod-
ification of the above heterocycles is a traditionally
important problem.
electrophilic substitution reactions such as formylation,
acylation, aminomethylation, azo coupling, halogena-
tion, etc. [4]. As in the indole series, all these reactions
involve exclusively the β-carbon atom of the pyrrole
ring (Scheme 1). According to the data of [4], the
nitration of 1a was less selective, and 6- or 7-nitro- or
6,7-dinitro derivative was obtained, depending on the
conditions. The goal of the present work was to study
in more detail the nitration of 1a and its 5-methyl
derivative 1b. The importance of this study is also
determined by the fact that, in keeping with the
We previously reported that 1,3-dimethylpyrrolo-
[3,2-d]pyrimidine-2,4-dione (1a) readily undergoes
Scheme 1.
O
O
R
R
Me
O
Me
O
N
N
HNO3 (1 equiv), H2SO4
N
N
+
NO2
N
N
O
4
R
5N
NO2
Me
Me
Me
O
HNO3, AcOH
3N
2a, 2b
3a, 3b
6
3a, 3b
2
N1
7
O
R
Me
Me
O
N
HNO3 (2.5 equiv), H2SO4
N
1a, 1b
NO2
N
NO2
Me
4a, 4b
R = H (a), Me (b).
1564

NITRO DERIVATIVES OF PYRROLO[3,2-d]PYRIMIDINE-2,4-DIONES:
Reaxys and SciFinder databases, 2,3-dinitroindoles
1565
C8
O1
H8A
remain so far unknown, whereas only a few data are
available on 2,3-dinitropyrroles [5–7]. On the other
hand, ortho-dinitro derivatives of this type should ob-
viously be obtainable from heterocyclic system like 1,
and the corresponding ortho-diamines are promising
substrates for further heterocyclizations. It was an ad-
ditional objective of our study to examine these
possibilities.
O4
C1
N1
O4A
N4
N2
C6
C5
C7
O3
C2
C3
We found that the nitration of 1a at 2–5°C with
a mixture of nitric acid (d = 1.4 g/cm3, 1 equiv) with
sulfuric acid afforded a mixture of 6- and 7-mononitro
derivatives 3a and 2a at a ratio of 1:13 in an overall
C4
O2
N4
1
yield of ~62% (according to the H NMR data; the
identification of isomers 2a and 3a by NMR spec-
troscopy was described in detail in [4]). When com-
pound 1a was treated with a nitrating mixture
containing 2.2 equiv of HNO3, the major product was
6,7-dinitro derivative 4a which was isolated in
53% yield. The nitration of 1a with excess nitric acid
in glacial acetic acid at 15–20°C gave only 6-nitro
derivative 3a in ~40% yield [4]. Thus, both mononitro
and dinitro derivatives of 1a can be selectively
obtained by varying the nitration conditions.
Fig. 1. Structure of the molecule of 1,3-dimethyl-7-nitro-
pyrrolo[3,2-d]pyrimidine-2,4(1H,3H)-dione (2a) according
to the X-ray diffraction data. Non-hydrogen atoms are shown
as thermal vibration ellipsoids with a probability of 50%
(crystallographic atom numbering is given).
tively. The corresponding deviation for the N4 atom is
somewhat larger (0.075 Å). The nitro group is slightly
turned with respect to the pyrrole ring, and the dihedral
angle C4C5N4O3 is 7.2(3)°. The X-ray diffraction data
for compound 2a are very consistent with the results of
DFT B3LYP/6-311G(d,p) calculations for the gas
phase (Table 1). The differences between the experi-
mental and calculated C–C, C–O, and C–N bond
lengths do not exceed 0.03 Å (except for the O4–N4
and O4–N4A bonds because of disordering of the
O4 atom).
1
Apart from the H NMR data, the structure of
7-nitro derivative 2a was proved by X-ray analysis
(Fig. 1, Table 1). The O4 atom in molecule 2a is dis-
ordered by two positions (O4 and O4A) with a popula-
tion ratio of 0.75:0.25. The bicyclic skeleton is almost
planar with the N2 atom deviating by 0.073 Å from the
mean-square plane fromed by the eight other atoms.
The O1, O2, and O3 atoms deviate from that plane
insignificantly, by 0.008, 0.055, and 0.003 Å, respec-
Molecules 2a in crystal form dimers through quite
strong intermolecular hydrogen bond N3–H3 ···O2i
(symmetry operation i: 0.5 – x, –1.5 – y, 2 – z; N3–H3
0.86, H3···O2 1.89, N3···O2 2.737(3) Å, ∠N3H3O2
167°). In addition, there are intermolecular hydrogen
bonds involving carbon atoms: C4–H4···O3ii (ii: 1 – x,
–2 – y, 2 – z; C4–H4 0.93, H4···O3ii 2.47, C4···O3ii
3.329(4) Å, ∠C4H4O3ii 153°) and C8–H8A · · · O4iii
Table 1. Experimental and calculated bond lengths in the
molecule of 1,3-dimethyl-7-nitropyrrolo[3,2-d]pyrimidine-
2,4(1H,3H)-dione (2a)
d, Å
calcd.
d, Å
exptl. calcd.
Bond
Bond
exptl.
O1–C1 1.219(3) 1.214 N2–C2 1.378(3) 1.400
O2–C2 1.235(3) 1.221 N2–C7 1.461(3) 1.468
O3–N4 1.217(3) 1.227 N3–C3 1.378(3) 1.375
O4–N4 1.285(3) 1.228 N3–C4 1.322(3) 1.341
O4A–N4 1.343(7)
–
N4–C5 1.412(3) 1.442
N1–C1 1.382(3) 1.403 C2–C3 1.420(3) 1.434
N1–C6 1.384(3) 1.383 C3–C6 1.378(3) 1.387
N1–C8 1.470(3) 1.472 C4–C5 1.389(3) 1.394
N2–C1 1.401(3) 1.403 C5–C6 1.431(3) 1.442
Fig. 2. Zigzag chains formed by molecules of 1,3-dimethyl-
7-nitropirrolo[3,2-d]pyrimidine-2,4(1H,3H)-dione (2a) in
crystal (view along the a crystallographic axis).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 10 2017

TKACHENKO et al.
1566
λ, nm
tives 3b, 2b, and 4b at a ratio of 1.2:5:1 (according to
the H NMR spectrum of the solid product separated
1
200
300
400
500 600
D/D0
from the reaction mixture). An additional amount of
more soluble 6-nitro derivative 3b (11%) was isolated
from the cold mother liquor after 2 days. In the
reaction of 1b with 3 equiv of HNO3 in H2SO4, the
major product was 6,7-dinitro compound 4b (yield
47%). Thus, the nitration of 1b is generally analogous
to the nitration of 1a with the difference that the yield
of the corresponding 6-nitro derivative in the nitration
of the former with HNO3 (1 equiv)–H2SO4 is slightly
higher. This may by rationalized by electron-donating
effect of the 5-methyl group, which increases the
electron density on C6 to a greater extent than on C7,
thus facilitating electrophilic substitution at the
α-position.
1.6
3a
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
3b
4a
4b
2a
50
45
40
35
30
25
20
15
ν, ×103 cm–1
The effect of the nitro groups on the π-electron
system of pyrrolopyrimidines 1a and 1b was estimated
by analysis of the electronic absorption spectra of the
obtained nitro derivatives (Fig. 3, Table 2). Table 2
also contains the theoretical absorption maxima of 3a
and 3b which were calculated (after preliminary AM1
optimization of the geometric parameters) by the
standard ZINDO method with special parameterization
for visualization of electronic transitions in the visible
and UV regions [8]. There is a good agreement
between the experimental and theoretical λmax values,
which indicates applicability of these computational
methods for the systems under study.
Fig. 3. Electronic absorption spectra of nitro derivatives 2–4.
(iii: 1 – x, y, 1.5 – z; C8–H8A 0.96, H8A ···O4iii 2.58,
C8···O4iii 3.402(4) Å, ∠C8H8AO4iii 143°). As a result,
infinite zigzag chains are formed (Fig. 2).
Taking into account that the nitration of 1a was not
selective, it seemed interesting to study the nitration of
its 5-methyl derivative. 1,3,5-Trimethylpyrrolo[3,2-d]-
pyrimidin-2,4(1H,3H)-dione (1b) was synthesized in
94% yield by alkylation of 1a with dimethyl sulfate in
aqueous alkali. The nitration of 1b with excess nitric
acid in acetic acid at room temperature gave only
6-nitro derivative 3b in a poor yield (6%). As in the
nitration of 1a under analogous conditions, we failed
to isolate 7-nitro isomer 2b, presumably due to insta-
bility of 7-nitro derivatives in HNO3–AcOH. The
nitration of 1b with an equimolar amount of nitric acid
(d = 1.4 g/cm3) in sulfuric acid led to the formation of
a mixture of 6-nitro, 7-nitro-, and 6,7-dinitro deriva-
The electronic spectrum of 1,3-dimethylpyrrolo-
[3,2-d]pyrimidine-2,4-dione (1a) in ethanol contains
two absorption bands with their maxima at λ 225 nm
(logε 4.05, sh) and 266 nm (logε 3.97) [9]. Intro-
duction of one nitro group into the 6-position gives rise
to a new absorption maximum at λ 368 nm, which is
likely to correspond to electronic transition from the
ring π-system to the nitro group. Although this
absorption maximum does not fall into the visible
region, the absorption tail extends to λ 400–410 nm,
which is responsible for the yellow color of 3a and 3b.
The absorption curve of 7-nitro derivative 2a is essen-
tially different: the long-wave absorption band looks
like a very broad and relatively low-intense shoulder,
probably because of considerable acoplanarity of the
7-nitro group. However, in this case the tail absorption
also reaches the visible region, thus endowing 2a with
yellow color. As might be expected, yellow 6,7-dinitro
derivatives 4a and 4b showed a red shift of the long-
wave absorption band; however, the magnitude of this
shift is fairly small, presumably due to steric hin-
drances and acoplanarity of two vicinal nitro groups.
Table 2. Absorption maxima and molar absorption coef-
ficients in the electronic spectra of nitro compounds 2a, 3a,
3b, 4a, and 4b in ethanol
Comp. Experimental Calculated Comp. Experimental
no. λmax, nm (logε) λmax, nm
no. λmax, nm (logε)
3a
243 (4.04)
303 (3.92)
368 (3.92)
245 (3.99)
306 (3.98)
368 (3.88)
248
293
362
247
305
367
2a
265 (4.14)
310 br sh
385 (3.84)
245 (3.95)
296 (3.73)
371 (3.78)
4a
4b
3b
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 10 2017

NITRO DERIVATIVES OF PYRROLO[3,2-d]PYRIMIDINE-2,4-DIONES:
1567
O
O
O
H
H
H
Me
O
Me
O
Me
O
N
N
N
N
N
N
NH2
NH2
N
N
N
NH2
NH2
Me
Me
6
Me
5
7
Nitro compounds 2a, 3a, and 4a were reduced to
the corresponding amines 5–7 in 50–69% yield by
treatment with sodium dithionite in aqueous ammonia.
Amines 5–7 were brought into reactions with di-
ketones to obtain various previously unknown poly-
nuclear heterocyclic systems. By heating 6-amino
derivative 5 with excess acetylacetone we obtained
42% of pyrimidopyrrolopyrimidine 8 (Scheme 2). In
Scheme 2.
Me
7
6
O
8
4
5N
Me
Me
O
O
O
3N
5
+
N9
Me
Me
2
N1
10
Me
8
O
H
O
Me
N
N
H
4
5 N
Me
Me
3 N
O
O
6
BF3·Et2O
O
N
6
+
Me
2
7
N
O
N1
Me
Me
Me
9 N
H
Me
8
O
Me
Me
9
10
Scheme 3.
O
O
H
O
O
H
13
11
14 N
12N
O
O
Me
O
Me
12N
10N
N15
2
N13
1
1
9
11
N10
Me
O
N8
Me
3
2
9 N
7N
8
4
3
8
6
5
4
5
7
6
11
12
7
Me
O
O
O
Me
Me
O
O
Ph
N
H
4
N
Ph
5 N
Me
N
3 N
Me
Me
O
N6
7
O
N
Me
2
O
N1
N
Ph
Me
9N
8
H
Me
Ph
O
Me
14
13
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 10 2017

TKACHENKO et al.
1568
the reaction of 7-amino derivative 6 with the same
diketone we succeeded in isolating the primary con-
densation product, enamino ketone 9, which readily
underwent cyclization to compound 10 (isomeric to 8)
on heating with boron trifluoride–diethyl ether
complex.
method and was refined against F2hkl by the full-matrix
least-square method in anisotropic approximation for
non-hydrogen atoms. Hydrogen atoms were placed
into geometrically calculated positions and were
refined according to the riding model [Uiso(H) =
nUeq(C), where n = 1.5 for methyl carbon atoms and
n = 1.2 for the other carbons]. Final divergence factors:
R1 = 0.0424, wR2 = 0.1165 [for 1140 independent
reflections with I > 2σ(I)], R1 = 0.0487, wR2 = 0.1234
(for all 1296 independent reflections); 154 variables;
goodness of fit 0.749. All calculations were performed
using SHELXL-97 [12], and the structure was ana-
lyzed by PLATON [13]. The crystallographic data for
compound 2a were deposited to the Cambridge Crys-
tallographic Data Centre (CCDC entry no. 1043985).
Likewise, diamine 7 reacted with diketones and
ortho-quinones (phenanthrenequinone, acenaphthene-
quinone, benzil, and acetylacetone) under conditions of
acid catalysis to give previously unknown heterocyclic
systems 11–14 in good yields (Scheme 3). In the
reactions with α-diketones, both amino groups of 7
behaved similarly, giving rise to a pyrazine ring,
whereas in the reaction with acetylacetone the NH2
groups behaved independently, so that enamine 14 was
formed. Compounds 8 and 10–14 in solution showed
intense blue, light blue, yellow, or yellow–green
fluorescence upon irradiation with UV light.
Quantum chemical calculations were performed at
the WSD and IBMX clusters of the High-Performance
Computations Joint Center of the Southern Federal
University using Gaussian 03 package [14]. The elec-
tronic and steric structure parameters were calculated
in terms of the density functional theory for the gas
phase using the B3LYP hybrid exchange correlation
functional [15–17] and 6-311G(d,p) extended split
valence basis set. The geometric parameters were
preliminarily optimized with respect to all natural
variables without symmetry restrictions. Minima on
the potential energy surface were identified by cal-
culating force constant and normal vibration matrices
for each structure.
Thus, we have synthesized 1,3-dimethyl-6,7-di-
nitropyrrolo[3,2-d]pyrimidine-2,4-diones which may
be regarded as representatives of a few but most acces-
sible α,β-dinitropyrrole compounds. The synthesized
compounds can be used to obtain many previously
unknown derivatives, in particular α,β-diaminopyrroles
and fused polycyclic systems based thereon.
EXPERIMENTAL
1
The H NMR spectra were recorded on a Bruker
DPX-250 spectrometer at 250 MHz using tetramethyl-
silane as internal standard. The IR spectra were
recorded on a Specord 75 IR spectrometer from
samples dispersed in mineral oil. The melting points
were measured in sealed capillaries with a PTP melting
point apparatus. The mass spectra (electron impact,
70 eV) were obtained on a Shimadzu GCMS-
QP2010SE instrument.
1,3,5-Trimethylpyrrolo[3,2-d]pyrimidine-
2,4(1H,3H)-dione (1b). A suspension of 1 g
(5.58 mmol) of compound 1a [4] in 10 mL of water
was heated to 40–50°C, and 2.82 g (22.4 mmol) of
dimethyl sulfate and a 4 N solution of 1.6 g (40 mmol)
of sodium hydroxide in water were added simultane-
ously with vigorous stirring at such rates that the tem-
perature did not exceed 60°C and pH did not exceed
9–10. The mixture was then stirred for 10 min, cooled,
and extracted with chloroform (5×4 mL). The solvent
was distilled off from the extract, and the residue
was recrystallized from water. Yield 1.01 g (94%),
colorless crystals, mp 169–170°C; published data [9]:
mp 171–172°C.
Single crystals of 2a suitable for X-ray analysis
were obtained by slowly cooling its solution in
acetone. Yellow plates; M 223.18; monoclinic crystal
system, space group C2/c; unit cell parameters (163 K):
a = 19.825(13), b = 5.795(3), c = 16.489(9)Å;
V = 1849.1(19) Å3; β = 102.53(5)°; Z = 8; dcalc
=
1.603 g/cm3. The unit cell parameters and intensities of
3711 reflections were measured on a Siemens P3
diffractometer (Mo Kα radiation, λ 0.71073Å, graphite
monochromator, φ- and ω-scanning, 2θmax = 46.12°)
from a 0.5×0.4×0.2-mm3 single crystal. The initial
data array was processed using SAINT [10] and
SADABS [11]. The structure was solved by the direct
1,3-Dimethyl-7-nitropyrrolo[3,2-d]pyrimidine-
2,4(1H,3H)-dione (2a). A solution of 1 g (5.58 mmol)
of compound 1a in 5 mL of concentrated sulfuric acid
was cooled to 2–5°C, and a mixture of 0.37 mL
(5.58 mmol) of nitric acid (d = 1.41 g/cm3) and 2 mL
of concentrated sulfuric acid was added dropwise with
vigorous stirring and cooling. The mixture was stirred
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 10 2017

NITRO DERIVATIVES OF PYRROLO[3,2-d]PYRIMIDINE-2,4-DIONES:
1569
for 1 h and poured onto 20 g of ice. After 30 min, the
precipitate was filtered off and washed with 10 mL of
water. Yield 0.77 g (62%, assuming formation of mono
b. Compound 1b, 0.39 g (2 mmol), was dissolved in
5 mL of glacial acetic acid, 1.5 mL (24 mmol) of nitric
acid (d = 1.42 g/cm3) was added dropwise with stirring
over a period of 10 min, and 10 mL of water was then
added. The mixture was stirred for 10 min and treated
with 2 g (24 mmol) of sodium hydrogen carbonate.
The light yellow crystals were filtered off and washed
with water. Yield 30 mg (6%), mp 210–211°C. The
product was identical in 1H NMR spectrum to a sample
obtained as described in a.
1
nitro derivatives). According to the H NMR data, the
product was a mixture of 6- and 7-nitro derivatives at
a ratio of 7:93. It was recrystallized from 55 mL of
ethanol to isolate 0.47 g (38%) of 7-nitro isomer 2a,
mp 272–273°C. IR spectrum, ν, cm–1: 3150 m (NH),
1710 s, 1680 s (C=O), 1575 s, 1390 s (NO2). 1H NMR
spectrum (DMSO-d6), δ, ppm: 3.25 s (3H, 1-CH3),
3.58 s (3H, 3-CH3), 8.27 d (1H, 6-H, J = 3.47 Hz),
13.55 br.s (1H, NH). Found, %: C 42.73; H 3.70;
N 24.88. C8H8N4O4. Calculated, %: C 42.86; H 3.60;
N 24.99.
1,3-Dimethyl-6,7-dinitropyrrolo[3,2-d]pyrimi-
dine-2,4(1H,3H)-dione (4a). A solution of 0.896 g
(5 mmol) of compound 1a in 4.5 mL of concentrated
sulfuric acid was cooled to 5°C, and a mixture of 2 mL
of concentrated sulfuric acid and 0.7 mL (11 mmol) of
nitric acid (d = 1.42 g/cm3) was added dropwise with
stirring. The mixture was stirred for 1.5 h on cooling
and poured onto 20 g of ice. The precipitate was
filtered off and washed with 5–10 mL of ice water.
Yield 717 mg (53%), yellow finely crystalline powder,
mp 278–279°C. IR spectrum, ν, cm–1: 3105 m (NH),
1710 s, 1660 s (C=O), 1563 s, 1358 s (NO2). 1H NMR
spectrum (DMSO-d6), δ, ppm: 3.21 s (3H, 1-CH3),
3.29 s (3H, 3-CH3), 14.55 br.s (1H, NH). Found, %:
C 35.83; H 2.60; N 25.93. C8H7N5O6. Calculated, %:
C 35.70; H 2.62; N 26.02.
The nitration of compound 1b was carried out as
described above for 1a. From 1.08 g (5.59 mmol) of
1b we obtained 0.8 g of a solid product which,
1
according to the H NMR data, was a mixture of
6-nitro (3b), 7-nitro (2b), and 6,7-dinitro derivatives
(4b) at a ratio of 1.2:5:1 with an overall yield of 60%
(calculated on mononitro derivatives).
1,3,5-Trimethyl-7-nitropyrrolo[3,2-d]pyrimidine-
2,4(1H,3H)-dione (2b) was isolated from the isomer
mixture obtained by nitration of 1b with an equimolar
amount of nitric acid in sulfuric acid. From 0.8 g of the
product mixture we isolated 0.48 g (~36%) of 2b
containing ~16% of 6,7-dnitro derivative 4b (accord-
1,3,5-Trimethyl-6,7-dinitropyrrolo[3,2-d]pyrimi-
dine-2,4(1H,3H)-dione (4b). A solution of 1.08 g
(5.6 mmol) of compound 1b in 4 mL of concentrated
sulfuric acid was cooled to 0–5°C, and a mixture of
1 mL (15.5 mmol) of nitric acid (d = 1.41 g/cm3) and
4 mL of concentrated sulfuric acid was added dropwise
with stirring over a period of 1 h. The mixture was
stirred for 30 min more and poured onto 40 g of ice.
The yellow crystals were filtered off and washed with
ice water. Yield 0.75 g (47%), mp 220–221°C. IR
spectrum, ν, cm–1: 1706 s, 1663 s (C=O), 1537 s,
1366 s (NO2). 1H NMR spectrum (DMSO-d6), δ, ppm:
3.28 s (3H, 1-CH3), 3.36 s (3H, 3-CH3), 4.32 s (3H,
5-CH3). Found, %: C 37.95; H 3.32; N 24.65. m/z 283
[M]+. C9H9N5O6. Calculated, %: C 38.17; H 3.20;
N 24.73. M 283.20.
1
ing to the H NMR data). Recrystallization from
acetone gave pure compound 2b. Yield 0.38 g (29%),
yellow crystals, mp 235–236°C. IR spectrum, ν, cm–1:
1710 s, 1670 s (C=O), 1540 s, 1350 s (NO2). 1H NMR
spectrum (DMSO-d6), δ, ppm: 3.26 s (3H, 1-CH3),
3.60 s (3H, 3-CH3), 3.99 s (3H, 5-CH3), 8.32 s (1H,
6-H). Found, %: C 45.42; H 4.30; N 23.21. m/z 238
[M]+. C9H10N4O4. Calculated, %: C 45.38; H 4.23;
N 23.52. M 238.20.
1,3,5-Trimethyl-6-nitropyrrolo[3,2-d]pyrimidine-
2,4(1H,3H)-dione (3b). a. The filtrate obtained in the
synthesis of 2b after separation of the isomer mixture
was left to stand for 2 days at 2–5°C. The yellow
precipitate was filtered off and washed with 3–5 mL of
water. It was pure 6-nitro isomer 3b. Yield 0.15 g
(11%), mp 210–211°C. IR spectrum, ν, cm–1: 1705 s,
6-Amino-1,3-dimethylpyrrolo[3,2-d]pyrimidine-
2,4(1H,3H)-dione (5). Compound 3a [4], 0.2 g
(0.89 mmol), was dissolved in 13 mL of 20% aqueous
ammonia on heating to 50–60°C, and 0.97 g
(5.6 mmol) of Na2S2O4 was added to the hot solution
over a period of 5 min. The mixture was heated to the
boiling point and was maintained slightly boiling for
1 min. After 10 min, the solution was cooled with ice
1
1676 s (C=O), 1570 s, 1380 s (NO2). H NMR spec-
trum (DMSO-d6), δ, ppm: 3.28 s (3H, 1-CH3), 3.42 s
(3H, 3-CH3), 4.34 s (3H, 5-CH3), 7.20 s (1H, 7-H).
Found, %: C 45.21; H 4.40; N 23.45. m/z 238 [M]+.
C9H10N4O4. Calculated, %: C 45.38; H 4.23; N 23.52.
M 238.20.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 10 2017

TKACHENKO et al.
1570
water. After 30 min, the colorless solid was filtered off,
washed with 10 mL of water and 2 mL of ethanol, and
dried at 100°C. Yield 0.12 g (69%), mp 253–254°C. IR
spectrum, ν, cm–1: 3380 m, 3329 m (NH, NH2), 1700 s,
1651 s (C=O). 1H NMR spectrum (DMSO-d6), δ, ppm:
3.17 s (3H, 1-CH3), 3.27 s (3H, 3-CH3), 5.07 d (1H,
7-H, J = 2.67 Hz), 5.52 br.s (2H, NH2), 10.56 br.s (1H,
NH). Found, %: C 49.56; H 5.20; N 28.63. m/z 194
[M]+. C8H10N4O2. Calculated, %: C 49.48; H 5.19;
N 28.85. M 194.19.
1 mL of ethyl acetate, and dried at 100°C. The product
showed blue fluorescence in DMSO solution and in the
solid state. Yield 45 mg (42%), light yellow crystals,
mp 262–263°C. IR spectrum, ν, cm–1: 3116 m
1
(C–Harom), 1686 s, 1648 s (C=O). H NMR spectrum
(CDCl3), δ, ppm: 2.50 s (3H, 8-CH3), 3.07 d (3H,
6-CH3, J = 0.77 Hz), 3.42 s (3H, 1-CH3), 3.53 s (3H,
3-CH3), 6.16 s (1H, 10-H), 6.49 br.d (1H, 7-H, J =
0.78 Hz). Found, %: C 60.32; H 5.31; N 21.38.
C13H14N4O2. Calculated, %: C 60.45; H 5.46; N 21.69.
7-Amino-1,3-dimethylpyrrolo[3,2-d]pyrimidine-
2,4(1H,3H)-dione (6) was synthesized in a similar
way from 0.3 g (1.34 mmol) of 2a in 20 mL of 20%
aqueous ammonia using 1.46 g (8.4 mmol) of
Na2S2O4. Yield 156 mg (60%), colorless powder,
mp 276–277°C. IR spectrum, ν, cm–1: 3379 m, 3323 m
1,3-Dimethyl-7-{[(Z)-1-methyl-3-oxobut-1-en-
1-yl]amino}pyrrolo[3,2-d]pyrimidine-2,4(1H,3H)-
dione (9). A mixture of 0.32 g (1.65 mmol) of amine 6
and 7 mL (68 mmol) of acetylacetone was refluxed for
3 h. After 24 h, the colorless solid was filtered off,
washed with 2–3 mL of ethanol, and dried at 100–
110°C. Yield 0.26 g (57%), mp 255–256°C. IR spec-
trum, ν, cm–1: 3152 m (NH), 1714 s, 1640 s, 1621 s
1
(NH, NH2), 1699 s, 1644 s (C=O). H NMR spectrum
(DMSO-d6), δ, ppm: 3.24 s (3H, 1-CH3), 3.51 br.s (2H,
NH2), 3.66 s (3H, 3-CH3), 6.66 d (1H, 6-H, J =
3.01 Hz), 11.21 br.s (1H, NH). Found, %: C 49.20;
H 5.86; N 28.90. m/z 194 [M]+. C8H10N4O2. Calculat-
ed, %: C 49.48; H 5.19; N 28.85. M 194.19.
1
(C=O). H NMR spectrum (DMSO-d6), δ, ppm: 1.78 s
(3H, CH3), 1.99 s (3H, CH3), 3.23 s (3H, 1-CH3),
3.35 s (3H, 3-CH3), 5.26 s (1H, CH), 7.32 s (1H, 6-H),
11.55 s (1H, NH), 12.28 br.s (1H, 5-H). Found, %:
C 56.34; H 5.90; N 20.35. C13H16N4O3. Calculated, %:
C 56.51; H 5.84; N 20.28.
6,7-Diamino-1,3-dimethylpyrrolo[3,2-d]pyrimi-
dine-2,4(1H,3H)-dione (7). Dinitro derivative 4a,
0.2 g (0.74 mmol), was dissolved in 10 mL of
20% aqueous ammonia on heating to 55–60°C, and
1.28 g (7.4 mmol) of Na2S2O4 was added in small
portions to the hot solution with stirring. The originally
dark yellow solution turned almost colorless. The
mixture was stirred for 5 min at 70–80°C and cooled to
2–5°C. After 30 min, the colorless crystalline solid was
filtered off, washed with 2–3 mL of water and ethanol
and dried at 100°C. The product darkened on
prolonged heating. Yield 77 mg (50%), mp >315°C. IR
spectrum, ν, cm–1: 3250 m (NH, NH2), 1690 s, 1630 s
1,3,6,8-Tetramethylpyrido[2′,3′:4,5]pyrrolo-
[3,2-d]pyrimidine-2,4(1H,3H)dione (10). A solution
of 0.1 g (0.36 mmol) of enamine 9 in 2 mL (20 mmol)
of acetylacetone was heated to the boiling point,
0.08 mL (0.63 mmol) of boron trifluoride–diethyl ether
complex was added, and the mixture was refluxed for
30 min. Light yellow needles separated from the mix-
ture. The mixture was cooled to room temperature, and
the precipitate was filtered off, washed with 2–3 mL of
ethanol, and dried at 100–110°C. The product showed
bright light blue fluorescence in DMSO solution and
greenish–yellow fluorescence in the solid state. Yield
56 mg (60%), mp >315°C. IR spectrum, ν, cm–1:
1
(C=O). H NMR spectrum (DMSO-d6), δ, ppm:
2.83 br.s (2H, NH2), 3.16 s (3H, 1-CH3), 3.65 s (3H,
3-CH3), 5.01 br.s (2H, NH2), 10.32 br.s (1H, NH).
Found, %: C 45.81; H 5.50; N 33.61. m/z 209 [M]+.
C8H11N5O2. Calculated, %: C 45.93; H 5.30; N 33.48.
M 209.21.
1
3245 m (NH), 1694 s, 1648 s (C=O). H NMR spec-
trum (CDCl3), δ, ppm: 2.53 s (3H, 8-CH3), 2.63 s
(3H, 6-CH3), 3.53 s (3H, 3-CH3), 4.17 s (3H, 1-CH3),
7.05 br.s (1H, 7-H), 10.84 br.s (1H, NH). Found, %:
C 60.27; H 5.82; N 21.50. C13H14N4O2. Calculated, %:
C 60.45; H 5.46; N 21.69.
1,3,6,8-Tetramethylpyrimido[4′,5′:4,5]pyrrolo-
[1,2-a]pyrimidine-2,4(1H,3H)-dione (8). A mixture
of 0.08 g (0.41 mmol) of amine 5 and 1 mL (9.8 mmol)
of acetylacetone was refluxed for 5 h. An additional
0.5 mL (4.9 mmol) of acetylacetone was added, and
the mixture was heated to the boiling point. The hot
mixture was filtered, the filtrate was evaporated, and
the residue was treated with 2–3 mL of ethyl acetate.
The undissolved material was filtered off, washed with
10,12-Dimethyldibenzo[f,h]pyrimido[4′,5′:4,5]-
pyrrolo[2,3-b]quinoxaline-11,13(10H,12H)-dione
(11). A solution of 0.1 g (0.48 mmol) of 9,10-phenan-
threnequinone in 6 mL of glacial acetic acid was
heated to the boiling point, 0.1 g (0.48 mmol) of
diamine 7 was added, and the mixture was refluxed for
10 min. A yellow solid separated from the mixture.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 10 2017

NITRO DERIVATIVES OF PYRROLO[3,2-d]PYRIMIDINE-2,4-DIONES:
1571
The mixture was cooled to room temperature, and the
precipitate was filtered off, washed with glacial acetic
acid, 5% aqueous sodium carbonate, water, and
ethanol, and dried at 100–110°C. The product showed
yellow fluorescence in DMSO solution and in crystal.
Yield 70 mg (83%), mp >320°C. IR spectrum, ν, cm–1:
pyrimidine-2,4(1H,3H)-dione (14). A mixture of
0.18 g (0.86 mmol) of diamine 7 and 2 mL (20 mmol)
of acetylacetone was refluxed for 3.5 h. An additional
1 mL (9.8 mmol) of acetylacetone was added, and the
mixture was heated to the boiling point and filtered
while hot. The filtrate was cooled, and the light yellow
crystals were filtered off, washed with 2–3 mL of
ethanol, and dried at 100–110°C. Yield 75 mg (25%).
The mother liquor was evaporated, the residue was
treated with 5–7 mL of ethyl acetate, and the undis-
solved material was filtered off, washed with 2–3 mL
of ethyl acetate, and dried at 100–110°C. We thus
isolated an additional 80 mg (26%) of enamine 14.
Overall yield 51%, mp 285–286°C. IR spectrum, ν,
1
3203 m (NH), 1702 s, 1660 s (C=O). H NMR spec-
trum (DMSO-d6), δ, ppm: 3.25 s (3H, 10-CH3), 3.63 s
(3H, 12-CH3), 7.55–7.77 m (4H, Harom), 8.55–8.64 m
(3H, Harom), 8.87 d (1H, 4-H, J = 7.92 Hz), 12.58 s
(1H, NH). Found, %: C 69.30; H 3.68; N 18.05.
C22H15N5O2. Calculated, %: C 69.28; H 3.96; N 18.36.
8,10-Dimethylacenaphtho[1″,2″:5′,6′]pyrazino-
[2′,3′:4,5]pyrrolo[3,2-d]pyrimidine-9,11(8H,10H)-
dione (12). A solution of 87 mg (0.48 mmol) of ace-
naphthenequinone in 6 mL of glacial acetic acid was
heated to 80–90°C, and 0.1 g (0.48 mmol) of diamine
7 was added. The mixture rapidly darkened, and a light
yellow solid precipitated. The suspension was refluxed
for 15 min and cooled to room temperature, and the
precipitate was filtered off, washed with glacial acetic
acid, 5% aqueous sodium carbonate, water, and
ethanol, and dried at 100–110°C. The product showed
yellow fluorescence in DMSO solution and in crystal.
Yield 142 mg (83%), mp 320°C (decomp.). IR spec-
trum, ν, cm–1: 3312 m (NH), 1692 s, 1648 s (C=O).
1H NMR spectrum (DMSO-d6), δ, ppm: 3.33 s (3H,
8-CH3), 4.08 s (3H, 10-CH3), 7.86–8.38 m (6H, Harom),
13.83 s (1H, NH). Found, %: C 67.58; H 3.52;
N 19.80. C20H13N5O2. Calculated, %: C 67.60; H 3.69;
N 19.71.
1
cm–1: 1694 s, 1666 s, 1614 s (C=O). H NMR spec-
trum (CDCl3), δ, ppm: 1.76 s (3H, CCH3), 2.12 s (3H,
COCH3), 2.50 s (3H, 8-CH3), 3.05 br.s (3H, 6-CH3),
3.43 s (3H, 1-CH3), 3.64 s (3H, 3-CH3), 5.31 s (1H,
CH), 6.54 br.d (1H, 7-H, J = 0.77 Hz), 11.77 br.s (1H,
NH). Found, %: C 60.50; H 5.84; N 19.40.
C18H21N5O3. Calculated, %: C 60.83; H 5.96; N 19.71.
REFERENCES
1. Corey, E.J., Czakó, B., and Kürti, L., Molecules and
Medicine, Hoboken, NJ: Wiley, 2007.
2. Pozharskii, A.F., Soldatenkov, A.T., and Katritzky, A.R.,
Heterocycles in Life and Society: An Introduction to
Heterocyclic Chemistry, Biochemistry, and Applications,
Chichester: Wiley, 2011, 2nd ed.
3. Gribble, G.W., Indole Ring Synthesis: From Natural
Products to Drug Discovery, Chichester: Wiley, 2016.
4. Tsupak, E.B., Tkachenko, Yu.N., and Pozharskii, A.F.,
Chem. Heterocycl. Compd., 1994, vol. 28, p. 1077.
5. Doddi, G., Mencarelli, P., Razzini, A., and Stegel, F.,
1,3-Dimethyl-7,8-diphenylpyrazino[2′,3′:4,5]-
pyrrolo[3,2-d]pyrimidine-2,4(1H,3H)-dione (13).
A solution of 0.202 g (0.96 mmol) of benzil in 4 mL of
glacial acetic acid was heated to the boiling point,
0.2 g (0.96 mmol) of diamine 7 was added, and the
mixture was refluxed for 30 min. The yellow precip-
itate was filtered off, washed with glacial acetic acid,
5% aqueous sodium carbonate, and water, and dried
at 100–110°C. The product showed greenish–yellow
fluorescence in DMSO solution and yellow fluores-
cence in crystal. Yield 183 mg (50%), mp 320–321°C.
IR spectrum, ν, cm–1: 3155 m (NH), 3109 m (C–Harom),
1703 s, 1663 s (C=O). 1H NMR spectrum (DMSO-d6),
δ, ppm: 3.32 s (3H, 1-CH3), 3.90 s (3H, 3-CH3), 7.30–
7.40 m (10H, Harom), 13.01 s (1H, NH). Found, %:
C 69.10; H 4.38; N 18.20. C22H17N5O2. Calculated, %:
C 68.92; H 4.47; N 18.27.
J. Org. Chem., 1979, vol. 44, p. 2321.
6. Grehn, L., Chem. Scripta, 1978, vol. 13, p. 67.
7. Jones, R.A. and Bean, G.P., The Chemistry of Pyrroles,
New York: Academic, 1977, p. 124.
8. CAChe 4.4 for Windows, USA: CAChe Group, Fujitsu
Systems
Business
of
America.
http:
www.cachesoftware.com
9. Senga, K., Ichiba, M., and Nishigaki, S., J. Org. Chem.,
1979, vol. 44, p. 3830.
10. SMART and SAINT, Release 5.0. Area Detector Control
and Integration Software, Madison (USA; Bruker AXS,
Analytical X-Ray Instruments, 1998.
11. Sheldrick, G.M., SADABS: A Program for Exploiting
the Redundancy of Area Detector X-Ray Data,
Göttingen (Germany), 1999.
1,3,6,8-Tetramethyl-10-{[(Z)-1-methyl-3-oxobut-
1-en-1-yl]amino}pyrimido[4′,5′:4,5]pyrrolo[1,2-a]-
12. Sheldrick, G.M., Acta Crystallogr., Sect. A, 2008,
vol. 64, p. 112.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 10 2017

TKACHENKO et al.
1572
13. Spek, A.L., J. Appl. Crystallogr., 2003, vol. 36, p. 7.
Strain, M.C., Farkas, O., Malick, D.K., Rabuck, A.D.,
Raghavachari, K., Foresman, J.B., Ortiz, J.V., Cui, Q.,
Baboul, A.G., Clifford, S., Cioslowski, J., Stefa-
nov, B.B., Liu, G., Liashenko, A., Piskorz, P.,
Komaromi, I., Martin, R.L., Fox, D.J., Keith, T., Al-
Laham, M.A., Peng, C.Y., Nanayakkara, A., Challa-
combe, M., Gill, P.M.W., Johnson, B., Chen, W.,
Wong, M.W., Gonzalez, C., and Pople, J.A., Gaussian
03, Revision D.01, Wallingford CT: Gaussian, 2003.
14. Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scu-
seria, G.E., Robb, M.A., Cheeseman, J.R., Mont-
gomery, J.A., Jr., Vreven, T., Kudin, K.N., Burant, J.C.,
Millam, J.M., Iyengar, S.S., Tomasi, J., Barone, V.,
Mennucci, B., Cossi, M., Scalmani, G., Rega, N.,
Petersson, G.A., Nakatsuji, H., Hada, M., Ehara, M.,
Toyota, K., Fukuda, R., Hasegawa, J., Ishida, M.,
Nakajima, T., Honda, Y., Kitao, O., Nakai, H.,
Klene, M., Li, X., Knox, J.E., Hratchian, H.P.,
Cross, J.B., Bakken, V., Adamo, C., Jaramillo, J.,
Gomperts, R., Stratmann, R.E., Yazyev, O., Austin, A.J.,
Cammi, R., Pomelli, C., Ochterski, J.W., Ayala, P.Y.,
Morokuma, K., Voth, G.A., Salvador, P., Dannen-
berg, J.J., Zakrzewski, V.G., Dapprich, S., Daniels, A.D.,
15. Stephens, P.J., Devlin, F.J., Chabalowski, C.F., and
Frisch, M.J., J. Phys. Chem., 1994, vol. 98, p. 11623.
16. Becke, A.D., J. Chem. Phys., 1993, vol. 98, p. 5648.
17. Lee, C., Yang, W., and Parr, R.G., Phys. Rev. B, 1988,
vol. 37, p. 785.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 10 2017