Transformation of the condensation products of 2-acylamino-3,3- dichloroacrylonitriles with imidazole into pyrazolo[1,5-a]pyrimidine derivatives

Article abstract of DOI:10.1134/S1070363209050223

Successive treatment of accessible 2-acylamino-3,3-dichloroacrylonitriles with imidazole and hydrazine hydrate led to the formation of 4-acylamino-3(5)-amino-5(3)-(1H-imidazol-1-yl)pyrazoles, and condensation of the latter with acetylacetone afforded 3-ac

Full text of DOI:10.1134/S1070363209050223

ISSN 1070-3632, Russian Journal of General Chemistry, 2009, Vol. 79, No. 5, pp. 996–1000. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © A.P. Kozachenko, O.V. Shablykin, E.B. Rusanov, A.N. Vasilenko, V.S. Brovarets, 2009, published in Zhurnal Obshchei Khimii,
2009, Vol. 79, No. 5, pp. 824–828.
Transformation of the Condensation Products
of 2-Acylamino-3,3-dichloroacrylonitriles with Imidazole
into Pyrazolo[1,5-a]pyrimidine Derivatives
A. P. Kozachenkoa, O. V. Shablykina, E. B. Rusanovb, A. N. Vasilenkoa, and V. S. Brovaretsa
a Institute of Bioorganic and Petroleum Chemistry, National Academy of Sciences of Ukraine,
ul. Murmanskaya 1, Kiev, 02660 Ukraine
e-mail: brovarets@bpci.kiev.ua
b Institute of Organic Chemistry, National Academy of Sciences of Ukraine,
ul. Murmanskaya 5, Kiev, 02660 Ukraine
Received July 1, 2008
Abstract—Successive treatment of accessible 2-acylamino-3,3-dichloroacrylonitriles with imidazole and
hydrazine hydrate led to the formation of 4-acylamino-3(5)-amino-5(3)-(1H-imidazol-1-yl)pyrazoles, and
condensation of the latter with acetylacetone afforded 3-acylamino-2-(1H-imidazol-1-yl)-5,7-dimethylpyrazolo
[1,5-a]pyrimidines whose structure was reliably determined by X-ray analysis.
DOI: 10.1134/S1070363209050223
More than 30 years ago it was reported that
accessible multicenter electrophiles, 2-acylamino-3,3-
dichloroacrylonitriles I, react in a specific mode with
primary and secondary amines, as well as with
pyrrolidine, piperidine, and morpholine, to give the
corresponding 5-amino-1,3-oxazole-4-carbonitrile deriv-
atives [1, 2]. In the present work we found that
reactions of compounds I with imidazole take a
different pathway. Instead of the expected trans-
formation sequence I → II → III, the process follows
alternative scheme I → II → IV (see below).
Presumably, the reaction of strongly basic imidazole
with intermediates II via nucleophilic replacement of
the labile chlorine atom by imidazole residue with
formation of compounds IV is faster than cyclization
of II to oxazoles III. The elemental compositions of
compounds IV were consistent with the assumed
structure (Table 1), and the presence of acylamino
group in their molecules was confirmed by the IR data
(Table 2). The structure of IV was also proved by
COSY, NOESY, HMQC, and HMBC heteronuclear
correlation spectra (Fig. 1, Table 3), which allowed us
to assign all 1H and 13C signals in their NMR spectra.
using two-dimensional HMQC and HMBC techniques,
we succeeded in not only assigning signals from
carbon atoms in both imidazole rings but also
determining the positions of poorly resolved signals
from 5-Ha and 4-Hb. The presence in the NOESY
spectrum of cross peaks at δ 9.54 (CONH)/7.86 ppm
(2-Hc, 6-Hc) and at δ 7.23 (5-Ha)/7.86 ppm (2-Hc, 6-
Hc) also supported the structure of IVb shown in Fig. 1.
Thus identification of compounds IV is beyond
doubt. 2-Acylamino-3,3-bis(1H-imidazol-1-yl)acrylo-
nitriles reacted with hydrazine hydrate on heating via
replacement of one imidazole residue by hydrazino
group and subsequent cyclization involving the cyano
group (transformation sequence IV → V → VI). The
IR spectra of the products lacked absorption band
typical of cyano group (Table 2), and the presence of
an amidine fragment in compounds VI was confirmed
by their cyclocondensation with acetylacetone, which
gave previously unknown 3-acylamino-2-(1H-imid-
azol-1-yl)-5,7-dimethylpyrazolo[1,5-a]pyrimidines VII.
The structure of one of these compounds was reliably
determined by X-ray analysis (Fig. 2).
Distribution of bond lengths and bond angles over
the N1–3C1–6 central bicyclic fragment of molecule
VIIb is typical of such fused heterocyclic systems;
nevertheless, we found only two analogous structures
It should be noted that assignment of signals from
the imidazole fragment was complicated by overlap of
the 5-Ha and 4-Hb signals (δ 7.23 ppm); nevertheless,
996

TRANSFORMATION OF THE CONDENSATION PRODUCTS
997
H
N
H
N
R
CN
Cl
R
CN
R
N
CN
N
N
2H
N
H
O
O
+
N
O
Cl
Cl
Cl−
Iа−Ic
IIа−IIc
IIIа−IIIc
N , Δ
3H
H
N
H
N
H
N
N
H
N
NH2
NH
R
C
N
R
CN
N
H2N−ΝΗ2
H2O, Δ
R
Δ
O
O
N
O
N
H
H
N
N
N
N
H
Vа−Vc
VIа−VIc
IVа−IVc
O
O
H
, Δ
N
Me
R
N
Me
Me
O
N
N
N
Me
VIIа−VIIc
H
N
H
H2N
N
N
Me
N
Me
N
(1) H3O+, (2) Na2CΟ3
PhN=C=S,
Δ
Ph
S
R = Me
N
N
N
N
N
Me
Me
VIII
IX
N = 1H-imidazol-1-yl.
R = Me (a), Ph (b), 4-MeC6H4 (c),
Table 1. Yields, melting points, and elemental analyses of compounds IV and VI–IX
Found, %
Calculated, %
H
Comp.
no.
Yield, %
mp, °C (solvent)
Formula
C
H
N
C
N
76
84
87
75
77
72
76
78
66
65
258–260 (THF)
202–204 (dioxane)
195–197 (dioxane)
243–245 (THF)
235–237 (THF)
255–257 (EtOH)
136–138 (EtOH)
200–202 (EtOH)
220–222 (C6H6)
>280 (EtOH)
54.22
62.93
64.38
58.51
59.23
57.85
64.82
66.12
57.64
59.22
4.02
3.91
4.52
4.29
4.95
5.00
5.04
5.42
4.96
5.01
34.32
27.31
26.13
31.09
30.02
31.44
25.08
24.61
37.01
26.56
C11H10N6O
C16H12N6O
C17H14N6O
C13H12N6O
C14H14N6O
C13H14N6O
C18H16N6O
C19H18N6O
C11H12N6
54.54
63.15
64.14
58.20
59.56
57.77
65.05
65.88
57.88
59.49
4.16
34.69
27.62
26.40
31.33
29.77
31.09
25.29
24.26
36.82
26.98
IVа
IVb
IVc
VIb
VIc
VIIа
VIIb
VIIc
VIII
IX
3.97
4.43
4.51
5.00
5.22
4.85
5.24
5.30
C18H17N7Sа
4.71
a
Found, %: S 8.63. Calculated, %: S 8.82.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 79 No. 5 2009

998
KOZACHENKO et al.
Table 2. IR and 1H NMR spectra of compounds IV and VI–IX
Comp.
no.
IR spectrum (KBr), ν, cm–1
1H NMR spectrum (DMSO-d6), δ, ppm
1690 (NC=O), 2237 (C=N), 3030–3170 (NHassoc
)
1.98 s (3H, CH3), 7.06–8.07 m (6H, Harom), 10.14 s (1H, NH)
7.03–8.15 m (11H, Harom), 10.58 s (1H, NH)
IVa
1660 (NC=O), 2255 (C=N), 3030–3200 (NHassoc
1670 (NC=O), 2240 (C=N), 3120–3260 (NHassoc
)
)
IVb
IVc
VIb
2.39 s (3H, CH3), 7.02–8.14 m (10H, Harom
)
1645a (NC=O, δ NH2), 2800–3260 (NHassoc), 3340, 5.10 br.s (2H, NH2), 6.96–7.96 m (8H, Harom), 9.40 s (1H, NH), 11.69 br.s
3425 (NH2) (1H, NH)
1645a (NC=O, δ NH2), 2800–3240 (NHassoc), 3300, 2.39 s (3H, CH3), 5.09 br.s (2H, NH2), 6.94–7.86 m (7H, Harom), 9.32 s
VIc
3400 (NH2)
(1H, NH), 11.66 br.s (1H, NH)
1660 (NC=O), 3060–3290 (NHassoc
)
2.10 s (3H, CH3), 2.53 s (3H, CH3), 2.69 s (3H, CH3), 6.94–8.08 m (4H,
Harom), 9.52 s (1H, NH)
VIIa
1655 (NC=O), 2900–3450 (NHassoc
1675 (NC=O), 3000–3275 (NHassoc
)
)
2.54 s (3H, CH3), 2.74 s (3H, CH3), 7.00–8.11 m (9H, Harom), 10.06 s (1H, NH)
VIIb
VIIc
2.41 s (3H, CH3), 2.52 s (3H, CH3), 2.72 s (3H, CH3), 6.98–8.13 m
Harom), 9.98 s (1H, NH)
(8H,
3270, 3370 (NH2)
2.49 s (3H, CH3), 2.61 s (3H, CH3), 4.00 br.s (2H, NH2), 6.72–8.29 m (4H, Harom)
VIII
IX
2900–3300 (NHassoc
)
2.57 s (3H, CH3), 2.71 s (3H, CH3), 6.98–8.19 m (9H, Harom), 9.15 br.s
(1H, NH), 10.22 br.s (1H, NH)
a
Band with a shoulder.
in the Cambridge Structural Database [3, 4]. The N1–3C1–6
central bicyclic fragment is almost planar: the mean-
square deviation of atoms from the plane is 0.014 Å
(the maximal deviation does not exceed 0.027 Å). The
N4C9N5C10C11 imidazole ring is turned through a
dihedral angle of 24.2° with respect to the above plane.
The C12–N6 bond [1.363(3) Å] is shorter than standard
single C–N bond (1.45 Å), and the sum of bond angles
C15
7.64
H
7.54
H
C16
C17
130.96
7.09
H
C8
C14
C13
119.76
7.23
133.37
N3
4
3
C6
7.86
N6
c
2
4
C12
2 C3
C5
C4
C18
129.35 5
128.59
H
H
C
5
N3
a
1
O1
6 132.77
H
9.54
C1
138.29
N1
N1
C11
2
C7
N
166.36
N2
97.7
7.84
N4
H
O2
C10
O
135.58
N 1
8.25
C9
H
C20
114.49
H
C19
2
N5
139.62
N
5
b
N3
7.52
120.91
Fig. 2. Structure of the molecule of compound VIIb (solvate
with ethanol) according to the X-ray diffraction data.
Principal bond lengths: C1–N2 1.334(3), C1–C2 1.404(3), C2–
C3 1.384(3), C3–N1 1.381(3), N1–N2 1.361(2), C1–N4 1.409(3),
C4–C5 1.352(3), C5–C6 1.412(3), C3–N3 1.356(3), C6–N3
1.319(3), C2–N6 1.411(3), C12–N6 1.363(3), C12–O1 1.227(3),
C4–N1 1.377(3), C9–N4 1.366(3), C9–N5 1.303(3), C10–N5
1.373(3), C10–C11 1.340(3), C11–N4 1.372(3) Å.
4
131.39
7.23
H
Fig. 1. Principal correlations (shown with arrows) and
chemical shifts of protons and carbon nuclei (δH, δC, ppm) in
the 1H and 13C NMR spectra of compound IVb.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 79 No. 5 2009

TRANSFORMATION OF THE CONDENSATION PRODUCTS
999
Table 3. Correlations in the COSY, NOESY, HMQC, and HMBC spectra of compound IVba
1H, δ, ppm
13C, δC, ppm
1H, δ, ppm
COSY
NOESY
7.54
HMQC
HMBC
7.64 (C4cH)
7.54
133.37
129.35
128.59
–
128.59 (C2c, C6c)
7.54 (C3cH, C5cH)
7.86 (C2cH, C6cH)
9.54 (CONH)
7.23 (C5aH)
7.86, 7.14
7.54
7.86, 7.64
129.35 (C3c, C5c), 132.77 (C1c)
7.23, 9.54, 7.54
128.59 (C2c, C6c), 133.37 (C4c), 166.36 (CO)
–
–
7.86
7.86, 7.09
7.23
–
7.09, 7.84
7.23, 7.84
7.09, 7.23
7.23, 8.25
7.52, 8.25
7.52, 7.23
119.76
130.96
138.29
120.91
131.39
139.62
130.96 (C4a), 138.29 (C2a), 135.58 (C=CCN)
138.29 (C2a)
7.09 (C4aH)
7.84 (C2aH)
119.76 (C5a), 130.96 (C4a)
131.39 (C4b), 139.62 (C2b), 135.58 (C=CCN)
139.62 (C2b)
7.52 (C5bH)
7.23
7.52
–
7.23 (C4bH)
8.25 (C2bH)
131.39 (C4b), 120.91 (C5b)
a
For numbering of carbon atoms in structure IVb, see Fig. 1.
at the N6 atom is 357.5(18)°; these data indicate
conjugation of lone electron pair on the N6 atom with
the carbonyl π-bond. Compound VIIb crystallizes as
solvate with ethanol. The solvate ethanol molecule is
linked to the carbonyl group through hydrogen bond
O2–H2···O1 [O1···O1 2.830(2), O2–H2 0.82(2),
N2···O1 2.012 Å, ∠ONO 174(2)°]. No shortened inter-
molecular contacts were found in the crystalline
structure of VIIb.
on a Varian Mercury-400 spectrometer from solutions
in DMSO-d6 using tetramethylsilane as internal
reference.
The X-ray diffraction data for a single crystal of
VIIb·EtOH, 0.06×0.26×0.29 mm, were acquired at
room temperature on a Bruker Smart Apex II diffracto-
meter (λMoKα irradiation, graphite monochromator,
θ
max = 26.29°, spherical segment 15 ≤ h ≤ 21, –8 ≤ k ≤
9, –16 ≤ l ≤ 16). Total of 11734 reflections were
measured, 3651 of which were independent (Rint
Unambiguous determination of the structure of com-
pound VIIb confirmed the structure of not only its
analogs VIIa and VIIc but also their precursors VIa–
VIc.
=
0.0412). Monoclinic crystal system, C20H22N6O2, M
378.44, space group P21/c (no. 14); unit cell param-
eters: a = 17.0575(9), b = 8.2334(4), c = 13.6631(7) Å;
β = 102.861(3)°; V = 1870.72(16) Å3; Z = 4; dcalc
=
To conclude, it should be noted that the acetyl
protection can be removed from compound VIIa by
acid hydrolysis. New heterocyclic base VIII thus
obtained can be modified by treatment with phenyl
isothiocyanate (as shown in scheme), as well as by
other reagents, which may be important from the
viewpoint of search for bioregulators among pyrazolo
[1,5-a]pyrimidine derivatives.
1.344 g cm–3; μ = 0.091 mm–1; F(000) = 800. The
structure was solved by the direct method and was
refined by the least-squares procedure in full-matrix
anisotropic approximation using SHELXS97 and
SHELXL97 software packages [4, 5]; 2333 reflections
with I > 2σ(I) were included in the refinement proce-
dure (314 refined parameters, 7.4 reflections per
parameter); weight scheme ω = 1/[σ2(Fo2) + (0.0712R)2 +
0.4247R], R = (Fo2 + 2Fc2)/3; the ratio of the maximal
(average) shift to the error in the last iteration was
0.001 (0.000). A correction for absorption was
EXPERIMENTAL
The IR spectra were recorded in KBr on a Specord
M-80 spectrometer. The 1H NMR spectra were
measured on a Varian VXR-300 instrument, and the 1H
and 13C NMR spectra of compound IVb were obtained
introduced using SADABS program (Tmin/Tmax
=
0.607417). All hydrogen atoms were localized from
the Fourier difference series, and their positions were
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 79 No. 5 2009

1000
KOZACHENKO et al.
refined in isotropic approximation. Only hydrogen
atoms on C20, O2, and C8 were localized on the basis of
geometry considerations. Protons in the methyl group
(C8H3) are disordered by two positions with equal
populations. The final divergence factors were R1(F2) =
0.0902, RW(F2) = 0.1429, goodness of fit 0.983 (all
reflections) and R1(F) = 0.0513, RW(F2) = 0.1230, GOF
0.983 [reflections with I > 2σ(I)]. The residual electron
density from the Fourier difference series after the last
iteration was 0.52 and –0.20 e Å–3. The complete set of
crystallographic data for compound VIIb was
deposited to the Cambridge Crystallographic Data
Centre (entry no. CCDC 690549).
toluene, and the mixture was heated for 5 h under
reflux. Volatile substances were removed under re-
duced pressure, and the residue was purified by recrys-
tallization from ethanol.
2-(1H-Imidazol-1-yl)-5,7-dimethylpyrazolo[1,5-a]-
pyrimidin-3-amine (VIII). A solution of 0.001 mol of
compound VIIa in 5 ml of concentrated hydrochloric
acid was heated for 6 h under reflux. The mixture was
evaporated under reduced pressure, the residue was
dissolved in 10 ml of water, 5 ml of a 10% aqueous
solution of sodium hydrogen carbonate was added, the
mixture was extracted with chloroform (2×10 ml), the
extract was dried over magnesium sulfate, the solvent
was removed under reduced pressure, and the residue
was purified by recrystallization from benzene.
2-Acylamino-3,3-bis(1H-imidazol-1-yl)acrylonitriles
IVa–IVc (general procedure). Imidazole, 0.6 mol, was
added to a solution of 0.1 mol of dichloroacrylonitrile
Ia–Ic in 200 ml of tetrahydrofuran, and the mixture
was heated for 8 h under reflux. The mixture was
cooled, the precipitate was filtered off, the solvent was
removed under reduced pressure, the residue was
treated with water, and the precipitate was filtered off
and purified by recrystallization.
N-[2-(1H-Imidazol-1-yl)-5,7-dimethylpyrazolo[1,5-
a]pyrimidin-3-yl]-N′-phenylthiourea (IX). Phenyl
isothiocyanate, 0.0055 mol, was added to a solution of
0.005 mol of compound VIII in 10 ml of acetonitrile.
The mixture was heated for 3 h under reflux, the
solvent was removed under reduced pressure, and the
residue was recrystallized from ethanol.
5-Amino-4-acylamino-3-(1H-imidazol-1-yl)-1H-
pyrazoles VIa–VIc (general procedure). Hydrazine
hydrate, 0.01 mol, was added to a solution of 0.005 mol
of compound IVa–IVc in 40 ml of tetrahydrofuran,
and the mixture was heated for 6 h under reflux and
left to stand for 12 h at 20–25°C. The precipitate was
filtered off, and the product was brought into further
syntheses without additional purification. Analytical
samples of compounds VIb and VIc were obtained by
recrystallization from tetrahydrofuran.
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RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 79 No. 5 2009