Synthesis of 1,3-dimethyl-2,4-dioxo-1H,2H,3H,4H-quinazolines and 1,5-dihydro-1,3-dimethyl-5-nitromethyl-2H- pyrano[4,3-d]pyrimidine-2,4(3H)-diones

Article abstract of DOI:10.1016/j.mencom.2009.07.016

5,7-Diaryl-1,3-dimethyl-2,4-dioxo-1H,2H,3H,4H-pyrano[4,3-d]pyrimidinium bromides react with malonodinitrile to form 1,3-dimethyl- 2,4-dioxo-1H,2H,3H,4H-quinazolines, whereas their reaction with nitromethane gives dihydro-1,3-dimethyl-5-nitromethyl-2H- pyr

Full text of DOI:10.1016/j.mencom.2009.07.016

Mendeleev
Communications
Mendeleev Commun., 2009, 19, 220–221
Synthesis of 1,3-dimethyl-2,4-dioxo-1H,2H,3H,4H-quinazolines
and 1,5-dihydro-1,3-dimethyl-5-nitromethyl-2H-
pyrano[4,3-d]pyrimidine-2,4(3H)-diones
Vladimir V. Kostrub,*a Evgeny B. Tsupaka and Yulia V. Nelyubinab
a Department of Chemistry, Southern Federal University, 344090 Rostov-on-Don, Russian Federation.
Fax: +7 863 297 5151; e-mail: dastr@yandex.ru
b A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 119991 Moscow,
Russian Federation. Fax: +7 499 135 5085; e-mail: unelya@xrlab.ineos.ac.ru
DOI: 10.1016/j.mencom.2009.07.016
5,7-Diaryl-1,3-dimethyl-2,4-dioxo-1H,2H,3H,4H-pyrano[4,3-d]pyrimidinium bromides react with malonodinitrile to form 1,3-dimethyl-
2,4-dioxo-1H,2H,3H,4H-quinazolines, whereas their reaction with nitromethane gives dihydro-1,3-dimethyl-5-nitromethyl-2H-
pyrano[4,3-d]pyrimidine-2,4(3H)-diones, the structure of one of them was established by X-ray analysis.
Recently, we reported the preparation of pyrimidopyrylium salts
and their reactions with N-nucleophiles.1,2 Pyrylium and benzo[c]-
pyrylium salts are capable of reacting with not only N- but also
C-nucleophiles.3,4 Pyrylium salts undergo recyclization involving
the cyano group of malonodinitrile, which yields o-aminocyano-
benzenes and 2-amino-3-cyanonaphthalenes. Monocyclic pyrylium
salts turn into nitrobenzenes upon treatment with nitromethane,3
while benzo[c]pyrylium salts give adducts – 1-nitromethylbenzo-
[c]pyrans.5
Here, we report the reaction of 5,7-diaryl-1,3-dimethyl-2,4-dioxo-
1H,2H,3H,4H-pyrano[4,3-d]pyrimidinium salts2 with malono-
dinitrile and nitromethane.
The reaction of bromides 1a–c with twice the amounts of
malonodinitrile and triethylamine results in their recyclization
into 7-amino-8-aroyl-6-cyano-1,3-dimethyl-2,4-dioxo-5-phenyl-
1H,2H,3H,4H-quinazolines 2a–c† (Scheme 1).
The structure of compounds 2a–c was established by 1H NMR
and IR spectra. The 1H NMR spectra contain deuterium-
exchangeable double proton singlets, which we believe to be
the signals of NH2 group. In the IR spectra, an absorption
maximum is observed at 2217–2219 cm–1, which is typical of a
CN group, and two absorption maxima are also found in the
regions 3303–3356 and 3422–3466 cm–1, which were assigned
to NH2 group.
The reaction of bromides 1a–c with nitromethane in the presence
of triethylamine afforded 7-aryl-1,5-dihydro-1,3-dimethyl-5-nitro-
methyl-5-phenyl-2H-pyrano[4,3-d]pyrimidine-2,4(3H)-diones
3a–c;‡ the structures of the products were suggested on the
basis of spectral data. The X-ray analysis of crystalline 3a§
proved that the reaction occurs at the 5-position (Scheme 2).
In line with the molecular geometry examination for 3a
(Figure 1), its bond lengths and angles fall into the range typical
†
The IR spectra of compounds were recorded on a Varian Excalibur 3100
Br–
O
Ph
O
Ph CH(CN)2
O
FT-IR spectrometer. The 1H NMR spectra were recorded on a Bruker
Avance DPX-250 spectrometer in CDCl3; HMDS was used as the internal
standard. Salts 1a–c were obtained according to published procedures.2
General procedure for the synthesis of compounds 2a–c. Triethylamine
(0.14 ml, 101 mg, 1 mmol) was added to a suspension of salts 1 (0.5 mmol)
and malonodinitrile (66 mg) in DMF (2 ml) and was kept for 4 h at room
temperature. H2O (4 ml) was added to the reaction mixture. The precipitate
formed was filtered off, dissolved in CHCl3 and passed through an aluminium
oxide column (eluent: CHCl3). A pale yellow fraction was collected and
evaporated to give the desired compound in a pure form.
2a: yield 52%, mp 237–239 °C. 1H NMR, d: 3.17 (s, 3H, N3Me), 3.23
(s, 3H, N1Me), 5.97 (s, 2H, NH2), 7.26–7.36 (m, 2H, Ph), 7.41–7.56 (m,
5H, Ph), 7.58–7.76 (m, 3H, Ph). IR (n/cm–1): 1606, 1666, 1712 (C=O),
2217 (CN), 3326, 3427 (NH2). Found (%): C, 70.41; H, 4.35. Calc. for
C24H18N4O3 (%): C, 70.23; H, 4.42.
2b: yield 65%, mp 275–278 °C. 1H NMR, d: 3.17 (s, 3H, N3Me), 3.24
(s, 3H, N1Me), 6.03 (s, 2H, NH2), 7.25–7.33 (m, 2H, Ph), 7.46–7.52
(m, 3H, Ph), 7.55 (d, 2H, Ar, J 8.76 Hz), 7.62 (d, 2H, Ar, J 8.83 Hz).
IR (n/cm–1): 1604, 1652, 1708 (C=O), 2219 (CN), 3303, 3422 (NH2).
Found (%): C, 59.13; H, 3.41; Br, 16.54. Calc. for C24H17BrN4O3 (%):
C, 58.91; H, 3.50; Br, 16.33.
2c: yield 56%, mp 231–233 °C. 1H NMR, d: 3.20 (s, 3H, N3Me), 3.24
(s, 3H, N1Me), 3.88 (s, 3H, OMe), 5.82 (s, 2H, NH2), 6.93 (d, 2H, Ar,
J 9.09 Hz), 7.25–7.34 (m, 2H, Ph), 7.43–7.55 (m, 3H, Ph), 7.63–7.76
(m, 2H, Ar). IR (n/cm–1): 1624, 1668, 1713 (C=O), 2219 (CN), 3356,
3466 (NH2). Found (%): C, 68.32; H, 4.69. Calc. for C25H20N4O4 (%):
C, 68.17; H, 4.58.
Me
Me
CH2(CN)2
Et3N
N
O
N
O
N
R
O
N
R
Me
Me
1a–c
O
Ph
Ph
O
Ph
Me
Me
CN
CN
N
N
Et3N
– H+
N
CN
R
O
N
O
N
N
R
Me
Me
O
O
O
O
O
Ph
Me
Me
CN
CN
H+
N
~ H+
O
N
N
O
N
NH2
H
R
Me
Me
O
R
2a–c
a R = Ph
b R = 4-BrC6H4
c R = 4-MeOC6H4
Scheme 1
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© 2009 Mendeleev Communications. All rights reserved.

Mendeleev Commun., 2009, 19, 220–221
O(22)
C(15)
Br–
C(19)
N(20)
O
Ph
O Ph CH2NO2
C(27)
C(28)
C(14)
Me
Me
C(26)
N
O
N
O
O(21)
MeNO2
Et3N
C(5)
C(24)
C(16)
C(23)
O
N
R
O
N
R
C(13)
C(18)
O(6)
C(4A)
C(7)
C(25)
Me
Me
O(12)
1a–c
C(4)
3a–c
C(17)
N(3)
a R = Ph
b R = 4-BrC6H4
c R = 4-MeOC6H4
C(8A)
C(8)
N(1)
C(10)
C(2)
Scheme 2
C(9)
of such a type of compounds. The introduction of CH2NO2 group
into the central cycle breaks the delocalization of electron density
over this fragment causing its conformation to vary from planar
one to a twist with the deviation of C(5) and O(6) atoms from the
C(7)–C(8)–C(8A)–C(4A) plane by 0.28 and 0.26 Å, respectively.
Nevertheless, the mutual disposition of phenyl and pyrimidine
rings is close to planarity; the corresponding dihedral angle is only
O(11)
Figure 1 General view of compound 3a in representation of atoms via
thermal ellipsoids (p = 50%). Selected bond lengths (Å): N(1)–C(2) 1.388(2),
C(2)–N(3) 1.382(2), N(3)–C(4) 1.403(2), C(4)–C(4A) 1.442(3), C(4A)–
C(8A) 1.366(2), N(1)–C(8A) 1.384(2), C(4A)–C(5) 1.516(2), C(5)–O(6)
1.453(2), O(6)–C(7) 1.368(2), C(7)–C(8) 1.343(2), C(8A)–C(8) 1.445(3);
selected bond angles (°): N(3)–C(4)–C(4A) 114.86(16), C(8A)–N(1)–C(2)
121.83(15), O(6)–C(5)–C(4A) 110.63(14), C(7)–C(8)–C(8A) 119.52(16).
‡
General procedure for the synthesis of compounds 3a–c: Triethylamine
12.3(3)°. This is apparently due to conjugation in the O(12)=C(4)–
C(4A)=C(8A)–C(8)=C(7)–Ph fragment, which appears from the
shortening of formally single C–C bonds down to 1.442(2) Å.
Although adduct 3a contains several atoms with high H-bonding
abilities, the absence of convenient proton-donor defines that
the molecules of 3a are held together only by weak contacts.
Thus, the aggregation of molecular species is mainly governed by
C–H···O interactions (C···O 3.265–3.566 Å), where the strongest
one is the NO2CH2 to C=O binding. Oxygen atoms of NO2CH2
fragment are also involved in the bifurcated C–H···O bond with
the intermediate values of C···O separation (3.450 and 3.448 Å).
In addition, the aromatic nature of R substituent (Scheme 2)
resulted in the formation of the C–H···π interactions (C···C 3.457–
3.671 Å), completing the 3D framework in the crystal of 3a.
Thus, 5,7-diaryl-1,3-dimethyl-2,4-dioxo-1H,2H,3H,4H-pyrano-
[4,3-d]pyrimidinium bromides react with C-nucleophiles yielding
derivatives of 1,3-dimethyl-2,4-dioxo-1H,2H,3H,4H-quinazolines
2a–c and 1,5-dihydro-1,3-dimethyl-5-nitromethyl-2H-pyrano-
[4,3-d]pyrimidine-2,4(3H)-diones 3a–c.
(0.14 ml, 101 mg, 1 mmol) was added to a suspension of salts 1 (0.5 mmol)
in MeNO2 (2 ml) and was heated to complete dissolution of initial salt.
After the reaction mixture was cooled, the precipitate formed was
filtered off and washed with MeNO2.
3a: yield 75%, mp 249–251 °C. 1H NMR, d: 3.46 (s, 3H, N3Me), 3.54
(s, 3H, N1Me), 5.15 (d, 1H, CH2, J 13.33 Hz), 6.18 (s, 1H, C8H), 6.37
(d, 1H, CH2, J 13.33 Hz), 7.30–7.39 (m, 3H, Ph), 7.41–7.58 (m, 5H, Ph),
7.75–7.88 (m, 2H, Ph). IR (n/cm–1): 1544 (C–NO2), 1649, 1693 (C=O).
Found (%): C, 65.05; H, 4.70. Calc. for C22H19N3O5 (%): C, 65.18; H, 4.72.
3b: yield 68%, mp 239–240 °C. 1H NMR, d: 3.42 (s, 3H, N3Me), 3.50
(s, 3H, N1Me), 5.09 (d, 1H, CH2, J 13.25 Hz), 6.13 (s, 1H, C8H), 6.32
(d, 1H, CH2, J 13.32 Hz), 7.26–7.42 (m, 5H, Ph), 7.54–7.68 (d + d, 4H,
Ar, J 8.76 Hz, J 8.75 Hz). IR (n/cm–1): 1553 (C–NO2), 1651, 1692 (C=O).
Found (%): C, 54.37; H, 3.81; Br, 16.73. Calc. for C22H18BrN3O5 (%):
C, 54.56; H, 3.75; Br, 16.50.
3c: yield 60%, mp 236–239 °C. 1H NMR, d: 3.42 (s, 3H, N3Me), 3.49
(s, 3H, N1Me), 3.86 (s, 3H, OMe), 5.11 (d, 1H, CH2, J 13.23 Hz), 6.03
(s, 1H, C8H), 6.31 (d, 1H, CH2, J 13.23 Hz), 6.96 (d, 2H, Ar, J 9.01 Hz),
7.26–7.35 (m, 3H, Ph), 7.36–7.47 (m, 2H, Ph), 7.74 (d, 2H, Ar, J 9.01 Hz).
IR (n/cm–1): 1548 (C–NO2), 1643, 1694 (C=O). Found (%): C, 63.68;
H, 4.76. Calc. for C23H21N3O6 (%): C, 63.44; H, 4.86.
§
Crystallographic data. Crystals of 3a (C22H19N3O5, M = 405.40) are
References
monoclinic, space group P21/n, at 120 K: a = 8.2649(5), b = 13.7977(8)
and c = 16.4066(9) Å, b = 93.636(5)°, V = 1867.19(19) Å3, Z = 4 (Z' = 1),
dcalc = 1.442 g cm-3, m(MoKα) = 1.04 cm–1, F(000) = 848. Intensities of
19853 reflections were measured with a Bruker SMART 1000 CCD
diffractometer [l(MoKα) = 0.71072 Å, w-scans, 2q < 58°] and 4953
independent reflections [Rint = 0.0283] were used in further refinement.
Structure was solved by a direct method and refined by the full-matrix
least-squares against F2 in anisotropic approximation for non-hydrogen
atoms. The H(C) atom positions were calculated and they were refined
in an isotropic approximation in riding model with the Uiso(H) parameters
equal to 1.2Ueq(Ci), for methyl groups equal to 1.5Ueq(Cii), where U(Ci)
and U(Cii) are respectively the equivalent thermal parameters of the carbon
atoms to which corresponding H atoms are bonded. For 3a, the refinement
converged to wR2 = 0.1488 and GOF = 1.004 for all independent reflections
[R1 = 0.0568 was calculated against F for 3590 observed reflections with
I > 2s(I)]. All calculations were performed using SHELXTL PLUS 5.0.6
CCDC 735640 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
For details, see ‘Notice to Authors’, Mendeleev Commun., Issue 1, 2009.
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Received: 12th December 2008; Com. 08/3249
– 221 –