Unusual reactions of 4,6-dichloro-5-nitropyrimidine with C-nucleophiles

Article abstract of DOI:10.1070/MC2005v015n05ABEH002156

The interaction of 4,6-dichloro-5-nitropyrimidine 1 with 1-phenyl-3-methylpyrazol-5-one led to the 4,6-dipyrazolyl derivatives of 5-nitropyrimidine 2 and dipyrazolylmethane 3; 2-methylindole reacts with 1 to form diindolylmethane 4 and trisindolylmethane

Full text of DOI:10.1070/MC2005v015n05ABEH002156

,
2005, 15(5), 193–196
Unusual reactions of 4,6-dichloro-5-nitropyrimidine with C-nucleophiles
a
b
b
b
Yuri A. Azev,* Thomas Duelcks, Enno Lork and Detlef Gabel
a
Ural State Technical University, 620002 Ekaterinburg, Russian Federation. Fax: +7 3432 51 6281; e-mail: azural@dialup.utk.ru
Department of Chemistry, University of Bremen, D-28334 Bremen, Germany. E-mail: duelcks@chemie.uni-bremen.de
b
DOI: 10.1070/MC2005v015n05ABEH002156
The interaction of 4,6-dichloro-5-nitropyrimidine 1 with 1-phenyl-3-methylpyrazol-5-one led to the 4,6-dipyrazolyl derivatives of
5
1
-nitropyrimidine 2 and dipyrazolylmethane 3; 2-methylindole reacts with 1 to form diindolylmethane 4 and trisindolylmethane 5;
,3-dimethylbarbituric acid displaces an indolyl residue in diindolylmethane 4 to form diheterylmethane 6.
1
4
,6-Bis(benzylthiopyrimidines) show an antitumor activity. The
purines and pteridines. The latter are constituents of natural
heterocyclic systems.3
Various 4,6-substituted 5-nitropyrimidines can be synthesised
starting from 4,6-dichloro-5-nitropyrimidine 1. Depending on
the nature of the nucleophile (O-, N- or S-nucleophile) and
reaction conditions, replacement products of one or two halogen
–5
anticarcinogenic action of condensed pyrimidines (purinethiols)
is related to their ability to be included in the nucleic acids of
2
tumoral cells.
o-Nitroamino-substituted pyrimidines are suitable starting
materials for the synthesis of condensed pyrimidines, such as
Mendeleev Commun. 2005 193

,
2005, 15(5), 193–193
Me
Me
O
Me
N
N
N
N
N
O
N
N
O
N
O
O HO
Me
Me
N
H
Me
Me
3
6
O
O
N
O
N
Me
NO2
Me
Me
NO2
N
N
N
N
N
N
NO2
N
N
O
HO
N
N
OH
Cl
Cl
Me Me
Me
H
H
Me
N
2
4
N
N
N
O
N
O
H
1
Me
O
H
H O
2
Me
N
H
Me
S
O
N
Me
O
O
Me
Me
S
N
N
Me
Cl
Cl
O
O
N
N
N
N
Me Me
Me
H
H
H
OH
Scheme 1
7
5
6
mass spectrum‡ and melting point with dipyrazolylmethane
described. The molecular mass of compound 2, as determined
atoms can be produced. In case of the reaction of 4,6-dichloro-
-nitropyrimidine 1 with C-nucleophiles, there is a substitution
8
5
of the hydrogen atom at C(2) of the pyrimidine cycle and
reduction of the nitro group at C(5), leading to the formation of
by mass spectrometry, corresponds to a disubstitution product.
In the 1H NMR spectrum, the signals of the methyl group
(2.26 ppm) and the phenyl protons (7.30–7.60 ppm) of 1-phenyl-
3-methylpyrazol-5-one are observed. The H-2 signal of the
pyrimidine nucleus is observed at 8.66 ppm.
As a result of short heating of compound 1 with a 2.5 mol
surplus of 2-methylindole in ethanol, the salt of (2-methylindol-
3-yl)methane with nitromalonodinitrile 4 and tris(2-methyl-
indol-3-yl)methane 5 were obtained.
2
-substituted 5-aminopyrimidines.7
We found new unusual transformations of 4,6-dichloro-
5
-nitropyrimidine 1 with C-nucleophiles. By the interaction of
†
compound 1 (Scheme 1) with 1-phenyl-3-methylpyrazol-5-one
in the presence of triethylamine in dimethyl sulfoxide at room
temperature, 4,6-dipyrazolyl derivatives of 5-nitropyrimidine 2
and dipyrazolylmethane 3 were obtained. Note that the inter-
action of 1 with pyrazolone proceeds with appreciable heating
of the reaction mixture and formation of compound 3 as the
‡
1
13
H and C NMR spectra were recorded on a Bruker DPX 200 spectro-
1
major product (40%). Compound 3 is identical by H NMR,
2
1
meter ([ H ]DMSO, 200 MHz for H) using DMSO as an internal standard.
6
EI mass spectra were measured on a Finnigan MAT 95 double-focusing
mass spectrometer. EI conditions: 70 eV electron energy and 200 °C
ion source temperature. ESI mass spectra were acquired on a Bruker
Esquire-LC ion trap mass spectrometer. Samples were dissolved in aceto-
†
Reaction of 4,6-dichloro-5-nitropyrimidine 1 with 1-phenyl-3-methyl-
pyrazol-5-one. 0.077 g (0.4 mmol) of compound 1, 0.1 ml of triethyl-
amine and 0.140 g (0.8 mmol) of 1-phenyl-3-methylpyrazol-5-one were
kept in 1 ml of DMSO for 48 h at 20–25 °C. Solid dipyrazolylmethane 3
was filtered off and recrystallised from ethanol. The mother liquor was
diluted (1:1) with water and acidified to pH 3–4. A precipitate filtered
and divided by preparative TLC on plates with kiselgel 60pf254. Eluent:
CH Cl . The disubstitution product 2 was taken from a zone with R 0.35.
–
5
–6
–3
nitrile at concentrations of ca. 10 to 10 mol dm and injected into the
–1
mass spectrometer via a syringe pump at a flow rate of 2 µl min . Spectra
were recorded in positive and negative ion modes for 1 min and averaged
to correct for signal fluctuations. Conditions were chosen such as to
minimise the degree of collision-induced fragmentation.
2
2
f
Reaction of 4,6-dichloro-5-nitropyrimidine 1 with 2-methylindole.
.102 g (0.53 mmol) of compound 1 was boiled with 0.170 g (1.30 mmol)
of 2-methylindole in 4 ml of ethanol for 35–40 min. The reaction
mixture was cooled in an ice bath; solid salt 4 was filtered off and
recrystallised from ethanol. The mother liquor was evaporated in a
vacuum. The solid was precipitated from a solution of DMSO–EtOH
1:1, 2 ml) with water (1 ml). Product 5 was filtered off and washed with
water.
Reaction of salt 4 with 1,3-dimethylbarbituric acid. 0.032 g (0.2 mmol)
of 1.3-dimethylbarbituric acid and 0.02 ml of triethylamine were added
to 0.038 g (0.1 mmol) of compound 4 in 0.5 ml of DMSO. The reaction
mixture was kept at 20–25 °C for 24 h, and then diluted with water
Compounds 2–7 gave satisfactory elemental analyses.
For 2: yield 5–10%, mp 118–120 °C. H NMR, d: 2.26 (s, 3H 2Me),
6.32 (s, 2H, 2OH), 7.30–7.60 (m, 10H, CHarom), 8.66 (s, 1H, H-2). MS,
m/z (%): 469 (28).
1
0
For 3: yield 35–40%. Compound 3 is identical to dipyrazolyl-
8
,10
metane.
1
(
For 4: yield 40–45%, mp 193–195 °C. H NMR, d: 2.91 (s, 6H, 2Me),
6.94 (m, 2H, 2CHarom), 7.29 (m, 2H, 2CHarom), 7.43 (m, 2H, 2CHarom),
7.64 (m, 2H, 2CHarom), 8.98 (s, 1H, –CH=), 13.81 (s, 2H, 2NH).
1
3
C NMR, d: 14.20, 114.43, 118.48, 124.51, 124.85, 125.58, 126.42,
139.31, 148.60, 161.60.
1
For 5: yield 10–15%, mp >300 °C. H NMR, d: 1.93 (s, 9H, 3Me),
6.10 (s, 1H, CH), 6.50–7.40 (m, 12H, CHindole), 1062 (s, 3H, 3NHindole).
MS, m/z (%): 403 (85).
(
1:6). The precipitate of 6 formed was filtered off. Product 7 was
precipitated from DMF with water.
1,3-Dimethyl-2,4,6-trioxohexahydropyrimidin-5-yl)dimethylsulfonium
betaine 7. To 0.058 g (0.3 mmol) of compound 1 in 0.5 ml of DMSO
.094 g (0.6 mmol) of 1.3-dimethylbarbituric acid was added. The reac-
1
(
For 6: yield 30–35%, mp >250 °C. H NMR, d: 2.55 (s, 3H, Me), 3.22
(s, 3H, Me), 3.25 (s, 3H, Me), 6.50–7.50 (m, 4H, CHindole), 8.57 (s, 1H,
0
Csp
3
H), 12.60 (s, 1H, NHindole). MS, m/z (%): 297 (100).
tion mixture was kept at 20–25 °C for 24 h. Solid 7 was filtered off and
washed with ethanol.
For 7: yield 65–70%. Compound 7 is identical to compound described
earlier.
1
1
1
94 Mendeleev Commun. 2005

,
2005, 15(5), 193–193
NO2
NO2
NO2
N
Me
Cl
H
Cl
Cl
N
Me
N
Cl
N
N
N
N
H
N
N
N
H
H
H
H
1
4
H
– HCl
Me
– HCl
Me
Me
Me
N
N
H
H
Scheme 2
The signals of 2-Me protons (2.91 ppm) and NH groups
13.81 ppm) in the H NMR spectrum of salt 4 are in the weak-
field region, which confirms the protonation of the diindolyl-
Interestingly, by reaction of salt 4 with 1,3-dimethylbarbituric
acid in DMSO in the presence of triethylamine, the replacement
of one indolyl moiety occurs to give product 6.
1
(
methane molecule. The signal of the =CH groups is observed at
In the EI spectrum of compound 6, an intense peak due to the
molecular ion at m/z 297 (100%) was observed.
3
8
.98 ppm. In the 1 C NMR spectrum, ten signals of the carbon
2
1
atoms of the diindolylmethane cation are observed ([ H ]DMSO,
In the H NMR spectrum, the signals of Me protons (2.55 ppm),
6
d: 14.20, 114.43, 118.48, 124.51, 124.85, 125.58, 126.42, 139.31,
CHarom (6.60–7.50 ppm) and indolyl NH groups (12.60 ppm)
are observed. Proton signals of the barbituric acid Me groups
are detected at 3.22 and 3.24 ppm. The pyrimidine ring H-2
proton signal is at 8.57 ppm. Note that a compound analogous
to 6, i.e., 1,3-dimethyl-5[(1H-indol-3-yl)methylidene]-2,4,6-
(1H,3H,5H)-pyrimidinetrione, was synthesised by heating indole
with 1,3-dimethyl-5-dimethylaminomethylidene-2,4,6-(1H,3H,5H)-
pyrimidinetrione in glacial acetic acid for 5 h.9
1
48.60 and 161.60) owing to the paired equivalence of the
indolyl fragments and the symmetry of the molecule.
The positive-ion electrospray ionisation (ESI) mass spectrum
of compound 4 showed only one peak at m/z 273, with the inten-
1
3
sity of the C isotopic peak indicating a number of 19 atoms.
The only major ion in the negative ion ESI mass spectrum
–
was m/z 110, which was attributed to [NO –C(CN) ] .
2
2
In the IR spectrum, the low frequency of the nitrile group
stretching vibration (KBr, 2215 and 2200 cm ) indicates the
We found unexpected transformations by studying the reac-
tion of compound 1 with 1,3-dimethylbarbituric acid in DMSO
at room temperature. As a result of this reaction, product 7 with
a molecular mass of 216.05686 and the empirical formula
C H N O S is formed. This empirical formula corresponds
–1
presence of the electron-accepting NO group at the α-carbon
2
atom of the malononitrile anion of salt 4. The absorption of the
–
1
NO group is observed at 1565, 1520, 1338 and 1320 cm .
2
8
12
2
3
The electron impact (EI) spectrum of compound 5 showed
to (1,3-dimethyl-2,4,6,-trioxohexahydropyrimidin-5-yl)dimethyl-
sulfonium betaine 7. The structure of betaine 7 crystals was
investigated by X-ray diffraction analysis (Figure 1).§
Thus, dimethylbarbituric acid reacts with DMSO, and com-
pound 1 acts as a dehydrating reagent.
9
an intense peak at m/z 403 (85%). Product 5 was identified
1
as tris(2-methylindol-3-yl)methane by H NMR spectroscopy
1
and melting point. Thus, the H NMR spectrum contains proton
signals of the indolyl moiety (6.50–7.40 ppm). The proton signal
3
at the sp -hybridised C(2) atom is also observed at 6.10 ppm,
It is interesting that the signal intensity of the proton at the
1
and it can serve as a diagnostic attribute for triheterylmethane
derivatives.
The mechanism of formation of salt 4 can be explained by
Scheme 2. The unusually easy reaction of 1 with indole can be
explained by evolving HCl, which catalyses indole addition and
disintegration of the intermediate.
C(2) atom at 9.17 ppm in the H NMR spectrum of compound 1
in DMSO decreases upon addition of water, and the intensity of
a weak signal at 8.45 ppm eventually increases. Similar changes
1
in the H NMR spectrum may be explained by the existence of
an equilibrium mixture of a covalent hydrate and unhydrated
form 1 in a DMSO solution.
It is obvious that tris(2-indol-3-yl)methane 5 results from
the addition of the third molecule of methylindole to diindolyl-
methane 4. Similar addition reactions of 1-phenyl-3-methyl-
References
1
Khimioterapiya zlokachestvennykh opukholei (Chemotherapy of malignant
tumours), ed. N. N. Blokhina, Meditsina, Moscow, 1977 (in Russian).
L. A. Grigorjan, M. A. Kabdrikjan, L. A. Srkojan, F. G. Arsenjan, G. M.
Stepanjan and B. T. Garibdzhanjan, Khim.-Farm. Zh., 2000, 8 (in
Russian).
1
0
pyrazol-5-one to diheterylmethanes were described earlier.
2
C(2)
S(1)
O(3)
§
Crystal data for 7. At 173(2) K, a crystal of C H N O S (0.50×
C(2a)
8
12
2
3
C(7)
×
0.10×0.10 mm) is monoclinic, a = 857.36(17), b = 692.60(14) and c =
C(1)
3
=
885.30(18) pm, b = 118.29(3)°, V = 0.46290(16) nm , space group P2 /m,
1
–3
–1
N(2)
C(3)
Z = 2, dcalc = 1.552 g cm , m = 0.332 mm , l = 71.073 pm, F(000) = 228,
diffractometer Siemens P4, q range for data collection 2.61–25.98°,
index ranges –10 £ h £ 10, –8 £ k £ 8, –10 £ l £ 10, reflections col-
lected 3592, independent reflections 976 (Rint = 0.1820), completeness
C(6)
O(1)
C(5)
N(1)
C(4)
2
to q = 25.98° 99.1%, refinement method full-matrix least-squares on F ,
data/restraints/parameters 976/0/86, Goodness-of-fit on F2 0.997, final
R indices [I > 2s(I)] R = 0.0651, wR = 0.1390, R indices (all data)
O(2)
1
2
R = 0.0854, wR = 0.1495, largest diff. peak and hole 0.526 and –
1
2
–
3
0
.522 eÅ . The structure was solved by direct methods, subsequent
Figure 1 Molecular structure of compound 7. Selected bond lengths (Å):
least-squares refinement located the positions of the remaining atoms in
the electron density maps. All non-hydrogen atoms were refined with
individual anisotropic deflection parameters. H-atoms were calculated
with common isotropic.
Atomic coordinates, bond lengths, bond angles and thermal param-
eters have been deposited at the Cambridge Crystallographic Data Centre
C(1)–C(7) 1.400(6), C(1)–C(3) 1.430(5), C(1)–S(1) 1.724(4), S(1)–C(2)
1.781(3), S(1)–C(2a) 1.781(3), C(3)–O(1) 1.222(5), C(3)–N(1) 1.409(5),
N(1)–C(5) 1.363(5), N(1)–C(4) 1.472(5), C(5)–O(2) 1.218(5), C(5)–N(2)
.395(5), N(2)–C(7) 1.416(5), N(2)–C(6) 1.456(5), C(7)–O(3) 1.238(5);
selected bond angles (°): C(7)–C(1)–C(3) 124.3(4), C(7)–C(1)–S(1) 114.8(3),
C(3)–C(1)–S(1) 120.9(3), C(1)–S(1)–C(2) 106.26(13), C(1)–S(1)–C(2a)
1
(
CCDC). These data can be obtained free of charge via www.ccdc.cam.uk/
1
06.26(13), C(2)–S(1)–C(2a) 102.6(2), O(1)–C(3)–N(1) 120.0(3), O(1)–
conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336 033; or deposit@ccdc.cam.ac.uk).
Any request to the CCDC for data should quote the full literature citation
and CCDC reference number 283414. For details, see ‘Notice to Authors’,
Mendeleev Commun., Issue 1, 2005.
C(3)–C(1) 125.5(4), N(1)–C(3)–C(1) 114.5(4), C(5)–N(1)–C(3) 125.1(3),
C(5)–N(1)–C(4) 116.5(4), C(3)–N(1)–C(4) 118.4(3), O(2)–C(5)–N(1)
121.7(4), O(2)–C(5)–N(2) 121.2(4), N(1)–C(5)–N(2) 117.1(4), C(5)–N(2)–
C(7) 123.8(4), C(5)–N(2)–C(6) 118.3(4), C(7)–N(2)–C(6) 117.9(3), O(3)–
C(7)–C(1) 126.6(4), O(3)–C(7)–N(2) 118.2(4), C(1)–C(7)–N(2) 115.2(3).
Mendeleev Commun. 2005 195

,
2005, 15(5), 193–193
L. Selic and B. Stanovnic, Tetrahedron, 2001, 57, 3159.
3
B. G. Elion, W. H. Lange and G. H. Hitchings, J. Am. Chem. Soc., 1956,
8, 2858.
9
7
10 Yu. A. Azev, O. V. Grjaseva and B. V. Golomolzin, Khim. Geterotsikl.
Soedin., 2003, 1678 [Chem. Heterocycl. Compd. (Engl. Transl.), 2003,
39, 1478].
4
5
W. R. Boon, W. G. M. Jones and G. R. Ramage, J. Chem. Soc., 1951, 96.
G. M. Makara, W. Ewing, Y. Ma and E. Wintner, J. Org. Chem., 2001,
66, 5783.
11 R. Gommpper and H. Euchner, Chem. Ber., 1966, 99, 527.
6
7
8
A. A. DeFusco and M. J. Strauss, J. Heterocycl. Chem., 1981, 18, 351.
F. L. Rose and D. J. Brown, J. Chem. Soc., 1956, 1953.
Yu. A. Azev, H. Neunhoeffer, S. Foro, H. Lindner and S. V. Shorshnev,
Mendeleev Commun., 1995, 229.
Received: 29th March 2005; Com. 05/2479
1
96 Mendeleev Commun. 2005