Synthesis of a new hetrocyclic system 7,8-dihydroimidazo[1,2-c][1,3] oxazolo[4,5-e]pyrimidine

Article abstract of DOI:10.1007/s10593-010-0635-6

2-(Acylaminocyanomethylene)imidazolidines are formed on interacting 2-acylamino-3,3-dichloro-acrylonitriles with ethylenediamine. The former are converted into new derivatives of oxazolo-[4,5-e]pyrimidine on treatment with trifluoroacetic acid, and then w

Full text of DOI:10.1007/s10593-010-0635-6

Chemistry of Heterocyclic Compounds, Vol. 46, No. 9, 2010
SYNTHESIS OF A NEW HETROCYCLIC SYSTEM
7,8-DIHYDROIMIDAZO[1,2-c][1,3]OXAZOLO[4,5-e]PYRIMIDINE
A. P. Kozachenko1, O. V. Shablykin1, A. N. Chernega2, and V. S. Brovarets1*
2-(Acylaminocyanomethylene)imidazolidines are formed on interacting 2-acylamino-3,3-dichloro-
acrylonitriles with ethylenediamine. The former are converted into new derivatives of oxazolo-
[4,5-e]pyrimidine on treatment with trifluoroacetic acid, and then with triethyl orthoformate.
Keywords: 5-aminooxazoles, 2-acylamino-3,3-dichloroacrylonitriles, trifluoroacetic acid, triethyl
orthoformate, ethylenediamine, heterocyclization.
While continuing investigations on the chemistry of 2-acylamino-3,3-dichloroacrylonitriles 2 we have
developed a simple and convenient method of synthesis of a new heterocyclic system, in which the oxazole ring
is annelated to a 2,3-dihydroimidazo[1,2-c]pyrimidine fragment.
Dichloroacrylonitriles 2, represented in the Scheme, are readily obtained from available adducts of
chloral with carboxylic acid amides 1 [1-4]. On interacting them with N-nucleophiles (primary aliphatic and
aromatic amines), as a rule, derivatives of 5-amino-4-cyanooxazole are formed [3, 5, 6]. Totatally differently,
interaction of the indicated reagents with 1,4-[N,N]-dinucleophiles occurs, for example with ethylenediamine.
Derivatives of 5-aminooxazole are not formed, but substitution occurs of the two chlorine atoms in reagents 2 by
the ethylenediamine fragment, which leads to the formation of an imidazolidine ring and the preparation of
products 3 (Table 1).
HN
Cl
H
H
H2N
R
N
H
N
NH2
1. CF3COOH
2. NaHCO3
1. SOCl2 (excess)
2. NaCN (excess)
R
N
R
N
H
N
CCl3
Cl
O
CN
2Et3N
O
CN
O
OH
3a–e
2a–e
1a–e
CF3COO
H
+
N
N
HN
N
N
HC(OEt)3
N
N
N
H
N
N
N
N
N
CF3COOH
H
R
R
O
R
O
4a–d
NH
O
NH2
N
R
O
5a–d
6a–d
7a–d
1–7 a R = Ph, b R = 2-MeC6H4, c R = 4-MeC6H4, d R = 4-ClC6H4; 1–3 e R = Me
_______
* To whom correspondence should be addressed, e-mail: brovarets@bpci.kiev.ua.
1Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, Kiev 02660,
Ukraine.
2Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev 02094, Ukraine.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1384-1390, September, 2010.
Original article submitted December 30, 2009.
1116
0009-3122/10/4609-1116©2010 Springer Science+Business Media, Inc.

In the IR spectra of compounds 3 there were absorption bands for the stretching vibrations of the carbonyl
group in the 1652-1673 cm-1 region, and also absorption bands for the CN bond in the 2149-2177 cm-1 region
(Table 2). In the 1H NMR spectra of these compounds signals were recorded for the NH group (6.55-6.85 ppm) and
also signals for the aromatic and aliphatic protons with appropriate ratios of integral intensities. In addition, one
of these compounds 3e was obtained previously by Japanese investigators [5], which raises no doubt as to the
structure of products 3.
As a result of the favorable disposition of the nitrile group and the acylamino residue in compounds 3
the possibility arises of an intramolecular cyclization under the action of trifluoroacetic acid (see [7-9]) into new
derivatives of oxazole 4, which exist preferentially in the tautomeric form 5. Attempts to introduce compound 3e
into this cyclization with an acetylamine residue were unsuccessful, a mixture of unidentified substances was
formed. A characteristic special feature of the IR spectra of compounds 5a-d was the presence in them of three
intense absorption bands in the 1592-1690 cm-1 region. One of them belongs to the C=N bond of the
imidazolidine ring, and two to a 5-aminooxazole fragment which is natural for a derivative of 5-aminooxazole
[10]. In addition, there were no singlet signals in the 2100-2200 cm-1 region, which indicates the involvement of
the nitrile group in the heterocyclization of 3 → 5.
TABLE 1. Characteristics of the Synthesized Compounds
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °C*
Yield, %
С
Н
N
3a
3b
3c
3d
3e
5a
5b
5c
5d
6a
6b
6c
6d
7a
7b
7c
7d
C12H12N4O
63.08
63.15
64.54
64.45
64.53
64.45
54.94
54.87
50.50
50.59
63.08
63.15
64.38
64.45
64.37
64.45
54.80
54.87
65.62
65.54
66.59
66.66
66.57
66.66
57.32
57.26
51.21
51.14
52.54
52.46
52.53
52.46
5.22
5.30
5.91
5.82
5.75
5.82
4.29
4.22
6.13
6.07
5.22
5.30
5.75
5.82
5.74
5.82
4.31
4.22
4.16
4.23
4.85
4.79
4.70
4.79
3.41
3.33
3.22
3.15
3.63
3.58
3.64
3.58
24.47
24.55
23.17
23.12
23.03
23.12
21.38
21.33
33.78
33.71
24.48
24.55
23.07
23.12
23.07
23.12
21.41
21.33
23.60
23.52
22.29
22.21
22.28
22.21
20.62
20.55
15.98
15.90
15.36
15.30
15.35
15.30
213-215
52
58
60
62
51
68
72
74
75
84
87
90
92
68
71
73
76
C13H14N4O
258-260
C13H14N4O
245-247
C12H11ClN4O
C7H10N4O
224-226
203-205*2
193-195
C12H12N4O
C13H14N4O
215-217
C13H14N4O
235-237
C12H11ClN4O
C13H10N4O
219-221
269-271
C14H12N4O
239-241
C14H12N4O
267-269
C13H9ClN4O
C15H11F3N4O3
C16H13F3N4O3
C16H13F3N4O3
C15H10ClF3N4O3
292-294
231-233 (dec.)
207-209 (dec.)
225-227 (dec.)
230-232 (dec.)
46.65
46.59
2.68
2.61
14.55
14.49
_______
*Solvents for recrystallization: 2-propanol (compounds 3a-e), ethanol–water,
1:1 (compounds 5a-d), ethanol (compounds 6a-d, 7a-d).
*2Agrees with the data of [5].
1117

TABLE 2. IR and Mass Spectra of the Synthesized Compounds
Compound
IR spectrum, , cm1
m/z [M]+
3a
3b
3c
3d
5a
5b
5c
5d
6a
6b
6c
6d
7a
7b
7c
7d
228
242
242
262
228
242
242
262
238
252
252
272
238
252
252
272
1652* (C=O), 2177 (CN), 31003300 (NH ass.)
1673* (C=O), 2149 (CN), 31503450 (NH ass.)
1655* (C=O), 2171 (CN), 32003450 (NH ass.)
1657* (C=O), 2155 (CN), 31303540 (NH ass.)
1605, 1630, 1681, 29403550 (NH ass.)
1603, 1633, 1690, 29103470 (NH ass.)
1592, 1638, 1678, 27403410 (NH ass.)
1596, 1644, 1676, 27503300 (NH ass.)
1691* (C=N)
1694* (C=N)
1688* (C=N)
1688* (C=N)
1672* (C=N), 1705 (C=O)
1674* (C=N), 1703 (C=O)
1677* (C=N), 1706 (C=O)
1670* (C=N), 1710 (C=O)
_______
* Band with shoulder.
TABLE 3. 1H NMR Spectra of the Synthesized Compounds
Com-
pound
Chemical shifts, δ, ppm*
3a
3b
3.42 (4Н, m, 2СН2); 6.56 (1Н, s, NH); 6.65 (1Н, s, NH); 7.39-7.92 (5Н, m, Нarom); 8.74 (1Н, s, NH)
2.36 (3Н, s, СН3); 3.43 (4Н, m, 2СН2); 6.48 (1Н, s, NH); 6.55 (1Н, s, NH);
7.18-7.50 (4Н, m, Н arom); 8.40 (1Н, s, NH)
3c
2.37 (3Н, s, СН3); 3.41 (4Н, m, 2СН2); 6.56 (1Н, s, NH); 6.61 (1Н, s, NH);
7.20-7.80 (4Н, m, Н arom); 8.66 (1Н, s, NH)
3d
3.36 (4Н, m, 2СН2); 6.66 (1Н, s, NH); 6.85 (1Н, s, NH); 7.52-7.93 (4Н, m, Н arom);
8.92 (1Н, s, NH)
5a
5b
5c
5d
6a
6b
4.12 (4Н, s, 2СН2); 7.64-8.00 (5Н, m, Н arom)*2
2.37 (3Н, s, СН3); 4.16 (4Н, s, 2СН2); 7.35-7.88 (4Н, m, Н arom)*2
2.40 (3Н, s, СН3); 4.15 (4Н, s, 2СН2); 7.36-7.92 (4Н, m, Н arom); 8.92 (1Н, s, NH)*2
4.11 (4Н, s, 2СН2); 7.65-8.05 (4Н, m, Н arom)*2
3.98-4.12 (4Н, m, 2СН2); 7.56-8.02 (5Н, m, Н arom); 8.14 (1Н, s, Н-2 pyrimidine)
2.66 (3Н, s, СН3); 3.97-4.15 (4Н, m, 2СН2); 7.41-7.97 (4Н, m, Н arom);
8.14 (1Н, s, Н-2 pyrimidine)
6c
6d
7a
2.38 (3Н, s, СН3); 3.97-4.13 (4Н, m, 2СН2); 7.38-7.89 (4Н, m, Н arom);
3.98-4.14 (4Н, m, 2СН2); 7.62-8.02 (4Н, m, Н arom); 8.15 (1Н, s, Н-2 pyrimidine)
4.19 (2Н, t, J = 9.7, СН2); 4.79 (2Н, t, J = 9.7, СН2); 7.67-8.15 (5Н, m, Н arom);
8.99 (1Н, s, Н-2 pyrimidine); 11.65 (1Н, br. s, N+–H)
7b
7c
7d
2.75 (3Н, s, СН3); 4.19 (2Н, t, J = 9.6, СН2); 4.79 (2Н, t, J = 9.6, СН2);
7.42-8.10 (4Н, m, Н arom); 8.91 (1Н, s, Н-2 pyrimidine); 11.67 (1Н, br. s, N+–H)
2.44 (3Н, s, СН3); 4.18 (2Н, t, J = 9.8, СН2); 4.78 (2Н, t, J = 9.8, СН2);
7.49-8.04 (4Н, m, Н arom); 8.97 (1Н, s, Н-2 pyrimidine); 11.58 (1Н, br. s, N+–H)
4.19 (2Н, t, J = 9.3, СН2); 4.79 (2Н, t, J = 9.3, СН2); 7.73-8.17 (4Н, m, Н arom);
8.99 (1Н, s, Н-2 pyrimidine); 11.70 (1Н, br. s, N+–H)
_______
*1H NMR spectra of compounds 3a-d, 6a-d, 7a-d were recorded in
DMSO-d6, and compounds 5a-d in CF3COOD.
*2 NH and NH2 exchanged.
1118

The presence of two nucleophilic centers (NH2 and NH) in compounds 5 was used by us to form a
pyrimidine ring. On heating derivatives of 5-aminooxazole 5a-d with triethyl orthoformate closure of the
pyrimidine fragment occurs fairly readily (cf. [11]) and derivatives of the new heterocyclic system 6 are formed
in high yield. In the IR spectra of compounds 6a-d the broad absorption bands of NH2 and NH groups in the
2700-3600 cm-1 region, characteristic of compounds 5a-d, have disappeared. At the same time the elemental
analysis and mass spectra show the involvement of the orthoformate fragment in the molecular composition of
the reaction products. In addition, in the 1H NMR spectra a singlet signal is present in the 8.14-8.15 ppm region,
which may be assigned with a high degree of probability to the H-2 proton of the pyrimidine ring. But all these
data may not indicate unequivocally the formation of the new heterocyclic system. Attempts to grow crystals of
compounds 6 for X-ray structural analysis were unsuccessful, consequently they were converted into
trifluoroacetates 7a-d and X-ray structural analysis was carried out on one of them. The general shape of the 7b
molecule and its main bond lengths and valence angles are given in Fig. 1 and in Table 4. The central tricyclic
system O(1)N(1-4)C(1-7) is approximately planar, the deviation of atoms from the mean square plane did not
exceed 0.047 Å. Furthermore, even the exocyclic benzene ring C(8-13), in spite of the obvious steric hindrance,
was practically coplanar with this system (the appropriate dihedral angle was only 3.2o), which is caused by
efficient π-π conjugation. The N(3) and N(4) atoms have a plane-trigonal bond configuration, the corresponding
sum of valence angles at these atoms amounts to 359.3 and 359.9o. A special feature of the crystal structure of
compound 7b is the formation of an extremely stable cationic–anionic hydrogen bond N(4)–H(4)··O(3) with
geometric parameters N···O 2.672(4), H···O 1.92(3) Å, NHO 148(3)o (mean statistical interatomic N···O distance
for hydrogen bonds of the N–H···O type is 2.89 Å [12]).
Fig. 1. General view of the compound 7b molecule.
TABLE 4. Main Bond Lengths (l) and Valence Angles (ω)
Bond
l, Å
Valence angles
, deg
1.297(5)
1.385(4)
1.339(5)
1.311(5)
1.351(5)
1.381(4)
1.489(4)
1.308(5)
1.467(5)
C(1)N(1)C(2)
103.7(3)
111.9(3)
109.6(3)
123.8(3)
111.9(3)
N(1)C(1)
N(1)C(2)
N(2)C(3)
N(2)C(4)
N(3)C(4)
N(3)C(5)
N(3)C(7)
N(4)C(5)
N(4)C(6)
C(3)N(2)C(4)
C(5)N(3)C(7)
C(4)N(3)C(5)
C(5)N(4)C(6)
1119

EXPERIMENTAL
1
The IR spectra of substances were recorded on a Vertex 70 spectrometer in KBr disks, the H NMR
spectra on a Varian 300 (300 MHz) instrument, internal standard was TMS, and mass spectra of compounds on
an Agilent 1100/DAD/MSD VL G1965 instrument. Melting points were measured on a Fisher-Johns instrument.
2-(Aroylaminocyanomethylene)imidazolidines 3a-d. Ethylenediamine (15 g, 0.25 mol) was added
with stirring to a suspension of one of compounds 2a-e (0.05 mol) in 2-propanol (100 ml), the solid dissolved,
after 3-5 min imidazolidines 3a-d were precipitated, were filtered off, washed with water, and purified by
recrystallization.
5-Amino-2-aryl-4-(4,5-dihydro-1H-imidazol-2-yl)-1,3-oxazoles 5a-d. A solution of one of compounds
3a-d (0.005 mol) in trifluoroacetic acid (10 ml) was stirred for 10 min, the excess of acid was removed in
vacuum, the residue was treated with 5% aqueous NaHCO3 solution, the solid was filtered off, washed with
water, and purified by recrystallization.
2-Aryl-7,8-dihydroimidazo[1,2-c][1,3]oxazolo[4,5-e]pyrimidines 6a-d. A solution of the appropriate
aminooxazole 5a-d in triethyl orthoformate (20 ml) was boiled for 20 min, the precipitated solid was filtered off,
washed with diethyl ether, and purified by recrystallization.
Trifluoroacetates of 2-Aryl-7,8-dihydroimidazo[1,2-c][1,3]oxazolo[4,5-e]pyrimidines 7a-d. One of
compounds 6a-d (0.002 mol) was dissolved in ethyl alcohol (20 ml), trifluoroacetic acid (1 ml) was added, the
solution stirred for 10 min, evaporated to dryness, and compounds 7a-d were purified by recrystallization.
X-Ray Structural Investigation of a monocrystal of compound 7b of dimensions 0.04×0.28×0.38 mm
was carried out at room temperature on a Bruker Apex II automatic CCD diffractometer (MoKα radiation,
λ = 0.71069 Å, θmax = 26.5o, -12 ≤ h ≤ 13, -24 ≤ k ≤ 24, -8 ≤ l ≤ 9). In all 12423 reflections (3226 independent
reflections, Rint = 0.01) were collected. Crystals of compound 7b were monoclinic, a = 11.1903(4), b = 19.5679(8),
c = 7.3233(3) Å, β = 95.598(2)o, V = 1595.9(1) Å3, M = 366.3, Z = 4, dcalc = 1.52 g/cm3, μ = 1.31 cm-1,
F(000) = 752, space group P1/2n (No. 14). The structure was solved by the direct method and refined by the
method of least squares in a full matrix anisotropic approximation using the CRYSTALS set of programs [13].
In the refinement 1473 reflections with I > 3σ(I) were used (239 parameters were refined, reflections per
parameter 6.2). All hydrogen atoms were made apparent from an electron density difference synthesis and were
included in the refinement with fixed positions and thermal parameters (with the exception of atom H(4),
participating in the intermolecular hydrogen bond, which was refined isotropically). The Chebyshev weighting
factor was used in the refinement [14] with five parameters, 0.65, 0.38, 0.55, 0.14, and 0.19. The final values of
the divergence factors were R = 0.047 and Rw = 0.047, GOOF 1.178. Residual electron density from the Fourier
difference series was -0.26 and 0.46 e/Å3. A complete set of X-ray structural data for compound 7b has been
deposited in the Cambridge structural data bank (deposit CCDC 785919).
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