Conversion of 2-aryl-4-dichloromethylen-5(4H)oxazolones to 5-acylamino-substituted pyrimidine bases

Article abstract of DOI:10.1134/S1070363209030256

Available polycentral unsaturated azlactones with 4-dichloromethylene group by successive treating with benzamidine and then with morpholine or its analogs were converted to substituted 5-acylamino-4-hydroxypyrimidines containing the residues of the corre

Full text of DOI:10.1134/S1070363209030256

ISSN 1070-3632, Russian Journal of General Chemistry, 2009, Vol. 79, No. 3, pp. 496–499. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © V.M. Prokopenko, V.N. Sviripa, S.G. Pil’o, V.S. Brovarets, A.N. Chernega, B.S. Drach, 2009, published in Zhurnal Obshchei
Khimii, 2009, Vol. 79, No. 3, pp. 506–509.
Conversion of 2-Aryl-4-dichloromethylen-5(4H)oxazolones
to 5-Acylamino-Substituted Pyrimidine Bases
V. M. Prokopenkoa, V. N. Sviripaa, S. G. Pil’oa, V. S. Brovaretsa,
A. N. Chernegab, and B. S. Dracha
a Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine,
ul. Murmanskaya 1, Kiev, 02660 Ukraine
e-mail: drach@bpci.kiev.ua
b Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev,Ukraine
Received July 30, 2008
Abstract―Available polycentral unsaturated azlactones with 4-dichloromethylene group by successive
treating with benzamidine and then with morpholine or its analogs were converted to substituted 5-acylamino-
4-hydroxypyrimidines containing the residues of the corresponding nitrogen bases in the position 6. The
structure of these cyclization products is consistent with the scheme of their preparation and has been
confirmed also by 1H NMR spectroscopy and XRD analysis.
DOI: 10.1134/S1070363209030256
Chlorine-containing unsaturated azlactones
I
not established reliably, but enamides III or IV are
probably the important precursors of recyclization.
Structure of the final cyclization products agrees with
1H NMR data (Table 2), and also with the results of X-
ray study of one of the compounds V where Ar = 4-
MeC6H4, R = H2N, N = O(CH2)4N. A general view of
this molecule, and also the main interatomic distances
and bond angles are presented in the figure.
presented in the scheme are formed easily from the
available chloralamides as described previously [1, 2].
Polycentral electrophilic reagents I have already found
application for preparation of derivatives of 1,3-
oxazole [1,3], 1,3-thiazole [4], 1,3,4-oxadiazole [5],
1,3,4-thiadiazole [6], oxazolo[4,5-d]pyrimidine [7],
and some other fused systems [8].
The central heterocycle N2N(3)C(9-12) is planar.
Deflections of atoms from the root-mean-square plane
do not exceed 0.046 Å. Benzene ring C1–6 is practically
orthogonal to this cycle, the corresponding dihedral
angle is 81.0°. N1, N2, and N5 nitrogen atoms within
the limits of experimental error have the flat trigonal
bond configuration while the bond configuration of N4
atom is the flattened pyramide. Sums of the
corresponding bond angles at these atoms are 358.9,
359.1, 357.3, and 349.8°, respectively. Conjugation of
the UEP of N1 atom with π-system of the C8=O1
double bond causes significant shortening of the N1–C8
bond [1.360(6) Å] as compared to the standard value
for the N(sp2)–C(sp2) bond (1.43-1.45 Å) [10].
Molecular conformation is quite favorable for such
interaction because O1–C8–N1–C9 torsion angle is only
~1.33°. Shortening of N4–C11 bond to 1.351(5) Å is
explained analogously.
In this study they were used in the development of
a peculiar method for preparation of new three- and
tetrafunctionalyzed pyrimidine derivaties as seen from
the structures I–V (see the scheme and Table 1). At
first the reagents I were converted by means of the
reported procedure [9] to 4,5-dihydro-1H-imidazol-5
(4)-one derivatives II which were heated with
morpholine, piperidine, or pyrrolidine to form the
corresponding 5-acylamino-substituted pyrimidine
bases V in the 40–67% yield.
In the complex transformation II→V three main
processes take place. At first one or two chlorine atoms
of dichloromethyl group in the compounds II are
substituted by the residues of nitrogen-containing
bases. The second step is the cleavage of the imida-
zoline ring, while the third one is the cyclization to
substituted pyrimidines. Sequence of these stages is
496

CONVERSION OF 2-ARYL-4-DICHLOROMETJYLEN-5(4H)OXAZOLONES
497
H
Cl
Cl
Cl
O
Cl
O
O
H2N
H2+N
Ar
N
H
Et3N
N
O
N
NH
+
R
Cl_
Ar
R
Ia, Ib
IIa_IId
2
N
H, Δ
H
H
N
N
Cl N
N N
R
R
O
O
2 N
H
NH
NH
Ar
N
H
Ar
N
H
O
O
IIIa_IIIn
IVa_IVn
N
N
R
O
N
H
Δ
NH
Ar
N
H
_
N
H
O
Va_Vn
I: Ar = Ph (a), 4-MeC6H4 (b). II: Ar = Ph (a, c), 4-MeC6H4 (b, d); R = Ph (a, b), H2N (c, d). III–V: Ar = Ph (a, c, e, h, j, l, m), 4-MeC6H4
(b, d, f, g, i, k, m); R = Ph (a, b, e, f, h, i, l–n); H2N (c, d, g, j, k); N = (CH2)4N (a–d), (CH2)5N (e–g), O(CH2)4 (h–k), PhCH2NH (l, m),
PhCH2CH2NH (n).
Table 1. Yields, constants, and elemental analysis data of the compounds synthesized Va–Vn
Found, %
H
Calculated, %
H
Comp. Yield,
mp, °C
Formula
no.
%
55
44
42
67
61
65
62
47
47
40
56
11
21
15
(solvent for crystallization)
С
N
С
N
69.98
70.57
60.19
61.33
70.57
71.11
62.37
67.01
67.67
57.14
58.35
5.59
15.54
14.96
23.40
22.35
14.96
14.42
21.39
14.88
14.35
22.21
21.26
>300 (DMF)
69.70
70.25
59.82
61.01
70.69
69.98
62.02
66.89
67.49
5.41
5.76
5.55
5.92
6.09
6.07
6.25
5.24
5.52
15.32
14.73
23.26
22.19
14.88
14.33
21.08
14.70
14.28
C21H20N4O2
C22H22N4O2
C15H17N5O2
C16H19N5O2
C22H22N4O2
C23H24N4O2
C17H21N5O2
C21H20N4O3
C22H22N4O3
C15H17N5O3
C16H19N5O3
C24H20N4O2
C25H22N4O2
C25H22N4O2
Vа
Vb
Vc
Vd
Ve
Vf
5.92
>300 (dioxane)
>300 (DMF)
5.72
6.11
276-278 (EtOH)
284–286 (EtOH)
300–302 (EtOH)
>300 (EtOH)
>300 (AcOH)
>300 (AcOH)
>300 (DMF)
5.92
6.23
6.47
Vg
Vh
Vi
5.36
5.68
5.43
56.89
58.18
5.21
5.67
22.15
21.11
Vj
5.81
288–289 (EtOH)
>300 (DMF)
Vk
Vl
72.50
72.92
72.01
4.90
5.23
5.19
14.02
12.43
13.38
72.71
73.15
5.08
5.40
14.13
13.65
>300 (DMF)
Vm
Vn
>300 (DMF)
73.15
5.40
13.65
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 79 No. 3 2009

498
PROKOPENKO et al.
Table 2. Spectral data of the compounds synthesized
Comp.
no.
1Н NMR spectrum, δ, ppm (DMSO-d6)
1.84 br.s, 3.64 br.s [8H, (CH2)4N], 7.50–8.20 m (10H, 2C6H5), 9.33 s (1H, NH), 12.20 br.s (1H, NH)
Vа
1.81 br.s, 3.61 br.s [8H, (CH2)4N], 2.38 s (3H, CH3), 7.30–8.16 m (9H, C6H5, C6H4), 9.22 s (1H, NH), 12.20 br.s (1H, NH)
Vb
Vd
1.71 br.s, 3.60 br.s [8H, (CH2)4N], 2.36 s (3H, CH3), 6.16 с (2H, NH2), 7.26–7.83 m (4H, C6H4), 8.83 s (1H, NH), 10.10 br.s (1H,
NH)
Veа 1.55 m, 3.65 br.s [10H, (CH2)5N], 7.44–8.15 m (10H, 2C6H5), 9.24 с (1H, NH), 12.27 br.s (1H, NH)
Vfа 1.53 br.s, 3.64 br.s [10H, (CH2)5N], 2.39 s (3H, CH3), 7.25–8.15 m (9H, C6H5, C6H4), 9.15 s (1H, NH), 12.26 br.s (1H, NH)
Vhа 3.61 m [8H, О(CH2)4N], 7.55–8.13 m (10H, 2C6H5), 9.36 s (1H, NH), 12.37 br.s (1H, NH)
2.40 s (3H, CH3), 3.61–3.67 m [8H, О(CH2)4N], 7.26–8.15 m (9H, C6H5, C6H4), 9.15 s (1H, NH), 12.29 br.s (1H, NH)
2.38 s (3H, CH3), 3.49 m [8H, О(CH2)4N], 6.17 br.s (2H, NH2), 7.24–7.82 m (4H, C6H4), 8.79 s (1H, NH), 10.27 br.s (1H, NH)
4.67 s (2H, CH2), 7.20–8.10 m (16H, 3C6H5, NH), 9.18 с (1H, NH), 12.15 br.s (1H, NH)
Vi
Vk
Vl
2.30 s (3H, CH3), 4.69 s (2H, CH2), 6.90 br.s (1H, NH), 7.20–8.10 m (14H, 2C6H5, C6H4), 8.8 br.s (1H, NH), 11.25 br.s (1H, NH)
Vm
2.88 br.s (2H, CH2), 3.65 br.s (2H, CH2), 6.67 br.s (1H, NH), 7.20–8.10 m (15H, 3C6H5), 9.01 с (1H, NH), 12.05 br.s (1H, NH)
Vn
a IR spectra of compounds Ve, Vf, and Vh, ν, cm–1: 1630 (NC=O), 3050–3400 (NHac).
Hence, the presented data confirm not only the
structure of compound Vk, but also of its close and
more remote analogs.
is an important extension of the existing methods of
the acylamino groups introduction in the position 5 of
pyrimidine bases (compare [11]).
Finally note that the sphere of application of the
chlorine-containing azlactones for preparation of 5-
acylamino-substituted pyrimidine bases is evidently
wider than it is established in this work, but the
attempts to involve some simplest primary and
secondary amines failed. Treating compounds II with
benzylamine and 2-phenylethylamine lead to low yield
of the final products V. Meanwhile even with the
above-mentioned limitations the transformation I→V
EXPERIMENTAL
IR spectra were obtained on a Specord M-80
1
spectrometer in KBr pellets. H NMR spectra were
taken on a Varian VXR-300 instrument in DMSO-d6
against internal TMS.
X-ray study of the single crystal of compound Vk
(0.07×0.31×0.49 mm) was carried out at room
temperature on an automatic CCD Bruker Apex II
O2
C2
O1
N2
C10
C3
C1 C8
N4
C9
C12
C7
C11
N1
C16
N3
C4
C6
N5
C13
C5
C14
C15
O3
General view of the molecule of compound Vk. Interatomic distances (Å) and bond angles (deg): O1–C8 1.212(5), C1–C8 1.486(6),
N1–C8 1.360(6), N1–C9 1.430(5), N2–C(10) 1.386(5), N2–C11 1.340(5), N3–C11 1.307(5), N3–C12 1.367(5), N4–C11 1.351(5); C8N1C9
121.24, C10N2C11 121.94, C11N3C-12 117.4(4).
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 79 No. 3 2009

CONVERSION OF 2-ARYL-4-DICHLOROMETJYLEN-5(4H)OXAZOLONES
499
diffractometer (MoKα-radiation, λ 0.71069 Å, θmax
24.4°, –20 ≤ h ≤ 18, –14 ≤ k ≤ 12, –16 ≤ l ≤ 16). 13950
reflections were collected (2617 independent, Rint
0.02). Crystals of compound Vk are rhombic, a
17.7261(7), b 12.3434(5), c 14.5632(6) Å, V 3186.4(2) Å3,
M 329.4, Z 8, dcalc 1.37 g cm–3, μ 0.98 cm–1, F(000)
1392, space group Pbcn (N 60). The structure was
solved by the direct method and refined by the root-
mean-square method in the full-matrix anizotropic
approximation using CRYSTALS complex of
programs [12]. In the refining procedure 1241 reflec-
tions with I > 2σ(I) were used (233 refined parameters,
number of reflections per one parameter 5.3). About
50% of hydrogen atoms were evaluated from the
differential synthesis of electronic density, the other
atoms were settled geometrically. All hydrogen atoms
were included in refining with fixed positional and
thermal parameters, only H1, H2, H41, and H42 atoms
were refined isotropically. During the refining the
Chebyshev weighting scheme [13] with five
parameters (1.20, 1.10, 1.11, 0.35, and 0.29) was used.
Final values of divergence factors are R 0.056, RW
0.059, GOF 1.167. Residual electronic density from
the differential Fourier synthesis is 0.23 and –0.20 e Å–3.
Complete set of X-ray data for the compound Vk was
deposited in the Cambridge bank of structural data
(CCDC 694987).
5-Acylamino-6-benzylamino(phenylethylamino)-
2-phenylpyrimidin-4(3H)-ones (Vl-Vn). A mixture
of 0.03 mol of one of compounds IIa and IIb and 0.3
mol of benzylamine or phenylethylamine in 20 ml of
dry dioxane was refluxed for 16 h. After cooling
solvent was removed in a vacuum, the residue was
treated with water, the precipitate was filtered off, and
compounds Vl-Vn were purified by crystallization.
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5-Acylamino-6-pyrrolidino(piperidino, morpho-
lino)-2-phenylpyrimidin-4(3H)-ones (Va, Vb, Ve,
Vf, Vh, Vi). A mixture of 0.03 mol of one of the
compounds IIa and IIb [9] and 0.6 mol of pyrrolidine,
piperidine, or morpholine was refluxed for 12 h. After
cooling the amine excess was removed in a vacuum,
the residue was treated with water, and the precipitate
formed was filtered off. Compounds Va, Vb, Ve, Vh,
and Vi were purified by crystallization.
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2-Amino-5-acylamino-6-pyrrolidino(piperidino,
morpholino)pyrimidin-4(3H)-ones (Vc, Vd, Vg, Vj,
Vk) were prepared analogously to Va, Vb, Ve, Vh,
and Vi from compounds IIc and IId.
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