Synthesis of 3(5)-amino-4-acylamino-5(3)-arylsulfanylpyrazoles and their fused derivatives on the basis of N-(2,2,2-trichloro-1-hydroxyethyl)benzamides

Article abstract of DOI:10.1007/s11176-005-0517-2

Addition products of carboxylic acid amides and trichloroacetaldehyde are readily converted into 3-arylsulfanyl-2-acylamino-3-chloroacrylonitriles which react with hydrazine hydrate to afford 3(5)-amino-5(3)-arylsulfanyl-4- acylaminopyrazoles. The presenc

Full text of DOI:10.1007/s11176-005-0517-2

Russian Journal of General Chemistry, Vol. 75, No. 11, 2005, pp. 1816 1820. Translated from Zhurnal Obshchei Khimii, Vol. 75, No. 11, 2005,
pp. 1902 1906.
Original Russian Text Copyright
2005 by Popil’nichenko, Pil’o, Brovarets, Chernega, Drach.
Synthesis of 3(5)-Amino-4-acylamino-5(3)-arylsulfanylpyrazoles
and Their Fused Derivatives on the Basis
of N-(2,2,2-Trichloro-1-hydroxyethyl)benzamides
S. V. Popil’nichenko*, S. G. Pil’o*, B. S. Brovarets*, A. N. Chernega**, and B. S. Drach*
* Institute of Bioorganic and Petroleum Chemistry, National Academy of Sciences of Ukraine, Kiev, Ukraine
** Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev, Ukraine
Received November 3, 2004
Abstract Addition products of carboxylic acid amides and trichloroacetaldehyde are readily converted
into 3-arylsulfanyl-2-acylamino-3-chloroacrylonitriles which react with hydrazine hydrate to afford 3(5)-
amino-5(3)-arylsulfanyl-4-acylaminopyrazoles. The presence of an amidine fragment in the latter makes them
capable of undergoing cyclocondensations with -dicarbonyl compounds and ethyl cyanoacetate.
Several synthetic approaches to various functional
derivatives of the 1,3-azole series have been develo-
ped on the basis of adducts formed by carboxylic acid
amides and trichloroacetaldehyde. These approaches
have been reviewed in [1] and reported in recent
publications [2 4]. In the present work we examined
a new line in the synthetic application of such adducts,
The cyclocondensation with acetylacetone (IV
V) is quite regioselective due to symmetric structure
of the -dicarbonyl reagent. The direction of condensa-
tions with ethyl acetoacetate (IV
VI) and ethyl
cyanoacetate (IV VII) is also beyond doubt. As
shown previously [7, 8], many other 3(5)-aminopyra-
zole derivatives react in just that way. Nevertheless,
in order to reliably prove the regioselectivity of the
in particular the transformation sequence I
II
transformations IV
VIII, the structure of the pro-
III IV (Scheme 1), which led to formation of
duct obtained by reaction of 3(5)-amino-4-p-toluoyl-
amino-5(3)-p-tolylsulfanylpyrazole with dimedone in
the presence of benzaldehyde was determined by
X-ray analysis. The molecule of condensation product
VIII (R = Ar = 4-CH3C6H4, Ar = Ph) is shown in
figure. The principal bond lengths ( ) and bond
angles (deg) are as follows: S1 C1 1.743(4), S1 C11
1.780(4), N1 N2 1.372(4), N1 C1 1.339(5), N2 C3
1.349(4), N2 C4 1.455(4), N3 C3 1.375(4), N3 C6
1.361(4), C1 C2 1.414(5), C2 C3 1.382(5), C4 C5
1.517(5), C5 C6 1.361(5), N4 C2 1.410(4), N4 C18
1.366(5), C1S1C11 102.7(2), N2N1C1 104.6(3),
N1N2C3 111.7(3), N1N2C4 121.4(3), C3N2C4 126.2(3),
C3N3C6 119.2(3), C2N4C18 122.4(3).
The central bicyclic system N1C1C2C3N3C6C5C4N2
cannot be regarded as planar: deviations of atoms
from the mean-aquare plane reach 0.160 . The six-
membered ring C5 C10 has a half-chair conformation
(the modified Cramer Pople parameters S, , and
[9] are 0.57, 3.8, and 44.8 , respectively). The
previously unknown 3(5)-amino-5(3)-arylsulfanyl-4-
acylaminopyrazoles. The first two stages in this
sequence were studied in [3, 5], while the reaction of
3-arylsulfanyl-2-acylamino-3-chloroacrylonitriles III
with hydrazine hydrate is reported for the first time.
Participation in the condensation with hydrazine
hydrate of the cyano group and labile chlorine atom
in substrates III follows from the analytical data of
the products (Table 1), as well as from comparison of
1
the H NMR and IR spectra of initial enamidonitriles
III and cyclization products IV (Table 2). It is quite
obvious that the transformation III
IV is a parti-
cular case of the well studied cyclocondensation of
-functionalized acrylonitriles with hydrazine and its
derivatives [6, 7]. Nevertheless, despite a wide scope
of application of this cyclization, participation therein
of sulfur-containing enamidonitriles III attract un-
doubted interest from the preparative viewpoint since
it gives rise to new functionally substituted pyrazoles
IV having an amidine fragment.
benzene rings C11 C16, C19 C24, and C28 C33 are
turned with respect to the bicyclic system N1C1C2C3
N3C6C5C4N through dihedral angles of 68.2, 36.2, and
87.1 , respectively. Molecules VIIId in crystal are
linked to solvate ethanol molecules through medium-
Pyrazoles IV are capable of reacting with various
-dicarbonyl compounds, as well as with ethyl cyano-
acetate, to produce previously unknown pyrazolo-
[1,5-a]pyrimidine derivatives V VII.
1070-3632/05/7511-1816 2005 Pleiades Publishing, Inc.

SYNTHESIS OF 3(5)-AMINO-4-ACYLAMINO-5(3)-ARYLSULFANYLPYRAZOLES
1817
Scheme 1.
(1) SOCl2;
NHCOR
C N
ArS<>
<>C=C
NHCOR
C N
Cl3C CH NHCOR (2) HCN, Et N Cl2C=C
3
ArSH, Et3N
>
>
Cl
OH
Ia, Ib
IIa, IIb
IIIa IIIc
H2NNH2 H2O (excess)
O
O
Me
Me
Ar
,
O
O
H
NHCOR
NH2
ArS
Me
Me
O
N
ArS
NHCOR
NH
N
ArS
NHCOR
O
O
H
O
N
IVa IVc
N
CN
EtO
Me
EtO
N
O
N
N
ArS
NHCOR
ArS
NHCOR
Ar
Me
Me
Me
Me
VIIa, VIIb, VIId
Va Vc
N
O
N
NH
NH
Me
VIa VIc
N
N
NH2
O
VIIa, VIIb
Ia, IIa, IIIa, IIIc, IVa, IVc, Va, Vc, VIa, VIc, VIIa, VIIIa, R = Ph; Ib VIIIb, VIIId, R = 4-MeC6H4; IIIa, IIIb, IVa,
IVb, Va, Vb, VIa, VIb, VIIa, VIIb, VIIIa, VIIIb, VIIId, Ar = 4-MeC6H4; IIIc VIc, Ar = 4-ClC6H4; VIIIa, VIIIb,
Ar = 4-ClC6H4; VIIId, Ar = Ph.
Table 1. Yields, melting points, and elemental analyses of compounds III VIII
Found, %
Calculated, %
Comp. Yield,
mp, C (solvent)
Formula
no.
%
C
H
N (Cl)
S
C
H
N (Cl)
S
IIIb
79
75
159 160 (EtOH) 63.48
162 165 (EtOH) 55.38
4.73
3.14
7.98
(10.40)
7.88
9.69
9.40
C18H15ClN2OS
63.06
4.41
2.89
8.17
(10.34)
8.02
9.35
9.18
IIIc
C16H10Cl2N2OS 55.03
(20.01)
17.01
16.27
16.34
(10.18)
14.39
13.89
13.58
(8.62)
14.29
13.94
13.71
(20.33)
IVa
IVb
IVc
61
68
60
192 193 (EtOH) 62.65
194 195 (EtOH) 63.50
190 191 (EtOH) 55.29
5.05
5.11
3.55
9.76
9.60
9.02
C17H16N4OS
C18H18N4OS
C16H13ClN4OS
62.94
63.88
55.73
4.97
5.36
3.80
17.27 9.88
16.55 9.47
16.25 9.30
(10.28)
14.42 8.25
13.92 7.96
13.70 7.84
(8.67)
14.35 8.21
13.85 7.93
13.63 7.80
(8.63)
Va
Vb
Vc
72
75
70
143 145 (PhMe) 67.84
168 169 (PhMe) 68.45
225 227 (PhMe) 61.24
4.98
5.28
4.25
8.18
7.91
7.60
C22H20N4OS
C23H22N4OS
C21H17ClN4OS
68.02
68.63
61.68
5.19
5.51
4.19
VIa
VIb
VIc
68
65
71
245 247 (AcOH) 64.35
241 243 (AcOH) 65.05
256 259 (AcOH) 58.15
4.59
4.83
3.56
8.09
7.72
7.67
C21H18N4O2S
C22H20N4O2S
C20H15N4O2S
64.60
65.33
58.46
4.65
4.98
3.68
VIIa
VIIb
VIIIa
58
54
70
253 255 (EtOH) 61.01
241 243 (EtOH) 61.85
223 225 (EtOH) 67.15
4.49
5.05
4.25
17.60
17.12
9.51
(5.95)
9.48
7.92
7.79
5.37
C20H17N5O2S
C21H19N5O2S
C32H29ClN4O2S 67.56
61.36
62.20
4.37
4.72
5.14
17.89 8.19
17.27 7.91
9.85 5.64
(6.23)
9.62 5.51
(6.09)
VIIIb 68 75 238 240 (EtOH) 67.88
VIIId 65 123 125 (EtOH) 71.96
5.27
5.83
5.49
5.72
C33H30ClN4O2S 68.09
5.19
5.70
(6.01)
10.11
C33H31N4O2S
72.37
10.23 5.85
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 11 2005

1818
POPIL’NICHENKO et al.
Table 2. IR and 1H NMR spectra of compounds III VIII
Comp.
no.
IR spectrum (KBr),a , cm
1H NMR spectrum, , ppm
1
IIIb
1655 (C=O); 2230 (C N); 3250 2.35 s (3H, CH3), 2.38 s (3H, CH3), 7.32 d (2H arom.) 7.35 d (2H arom.), 7.45 d
(NHas) (2H arom.), 7.84 d (2H arom.), 10.48 s (1H, NH)
IVb
IVc
Va
1640b [C=O, (NH2)]; 3250, 2.22 s (3H, CH3), 2.37 s (3H, CH3), 4.63 br.s (2H, NH2), 7.05 q (4H arom.),
3310, 3400 (NH, NH2) 7.22 d (2H arom.), 7.77 d (2H arom.), 9.31 br.s (1H, NH), 12.01 (1H, NH)
1650b [C=O, (NH2)]; 3200, 4.74 br.s (2H, NH2), 7.13 7.50 m (7H arom.), 7.87 d (2H arom.), 9.43 br.s (1H,
3350, 3440 (NH, NH2)
NH), 12.17 br.s (1H, NH)
1645 (C=O); 3250 (NHac)
2.25 s (3H, CH3), 2.55 s (3H, CH3), 2.65 s (3H, CH3), 6.87 s (1H, C6 H), 7.05 d
(2H arom.) 7.27 d (2H arom.), 7.46 m (3H arom.), 7.93 d (2H arom.), 9.81 s
(1H, NH)
Vb
Vc
1670 (C=O); 3050 3300 (NHac) 2.25 s (3H, CH3), 2.40 s (3H, CH3), 2.64 s (3H, CH3), 6.86 s (1H, C6 H), 7.04 d
(2H arom.), 7.26 d (4H arom.), 7.84d (2H arom..), 9.72 s (1H, NH)
1655 (C=O); 3100 3350 (NHac) 2.51 s (3H, CH3), 2.67 s (3H, CH3), 6.91 s (1H, C6 H), 7.24 7.95 m (9H arom.),
9.88 s (1H, NH)
VIa
1635, 1680 (C=O); 3050 3400 2.23 s (3H, CH3), 2.30 s (3H, CH3), 5.56 s (1H, C6 H), 7.04 d (2H arom.),
(NHac)
7.27 d (2H arom.), 7.48 d (3H arom.), 7.91 d (2H arom.), 9.63 s (1H, NH),
11.94 s (1H, NH)
VIb
1640, 1690 (C=O); 3050 3400 2.24 s (3H, CH3), 2.30 s (3H, CH3), 2.40 s (3H, CH3), 5.56 s (1H, C6 H), 7.04 d
(NHac)
(2H arom.), 7.25 d (2H arom.), 7.28d (2H arom.), 7.81 d (2H arom.), 9.54 s (1H,
NH), 11.93 s (1H, NH)
VIc
1640, 1690 (C=O); 3050 3400 2.31 s (3H, CH3), 5.61 s (1H, C2 H), 7.28 d (2H arom.), 7.33 d (2H arom.),
(NHac) 7.48 d (3H arom.), 7.91 d (2H arom.), 9.70 s (1H, NH), 12.04 s (1H, NH)
1640, 1675 (C=O); 3050 3450 2.20 s (3H, CH3), 2.36 s (3H, CH3), 4.91 s (1H, C6 H), 7.05 d (2H arom.),
VIIb
(NH, NH2 ac)
7.23 d (2H arom.), 7.27 d (2H arom.), 7.34 br.s (2H, NH2), 7.75 d (2H arom.),
9.46 s (1H, NH), 11.41 br.s (1H, NH)
VIIIa 1655 (C=O); 3270, 3400 (NH) 0.94 s (3H, CH3), 1.07 s (3H, CH3), 2.08 2.30 m (4H, 2CH2), 2.49 s (3H, CH3),
6.18 s (1H, C9 H), 6.92 7.91 m (13H arom.), 9.51 s (1H, NH), 10.19 s (1H, NH)
VIIIb 1665 (C=O); 3240, 3420 (NH) 0.94 s (3H, CH3), 1.07 s (3H, CH3), 2.08 2.49 m (4H, 2CH2), 2.19 s (3H, CH3),
2.38 s (3H, CH3), 6.18 s (1H, C9 H), 6.91 d (2H arom.), 6.98 d (2H arom.),
7.16 d (2H arom.), 7.25 d (2H arom.), 7.30 d (2H arom.), 7.79 d (2H arom.),
9.40 s (1H, NH), 10.15 s (1H, NH)
VIIId 1665b (C=O); 3245, 3400 (NH) 0.92 s (3H, CH3), 1.04 s (3H, CH3), 2.10 2.55 m (4H, 2CH2), 2.16 s (3H, CH3),
2.36 s (3H, CH3), 6.21 s (1H, C9 H), 6.93 7.84 m (13H arom.), 9.50 s (1H, NH),
10.26 s (1H, NH)
a
1
1
Given are strong absorption bands in the regions 1600 1800 and 3050 3600 cm and also in the region 2200 2300 cm for
b
compounds IIIa and IIIb.
With a shoulder.
strength intermolecular hydrogen bonds N4 H O3
with the following parameters: N O 2.946(4), N H
EXPERIMENTAL
1.01(4)
,
NHO 161(2) ].
The IR spectra were recorded on a Specord M-80
spectrometer from samples prepared as KBr pellets.
The H NMR spectra were measured on a Varian
VXR-300 instrument from solutions in DMSO-d6
using TMS as internal reference.
1
To conclude, it should be noted that further modi-
fication of the arylsulfanyl groups and acylamino
fragments in accessible fused substrates V VIII may
be useful from the viewpoint of synthesis of new
pyrazolo[1,5-a]pyrimidine derivatives. Studies in this
line will be the subject of our subsequent publications.
A single crystal of compound VIIId (0.29 0.31
0.49 mm) was examined at room temperature on an
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 11 2005

SYNTHESIS OF 3(5)-AMINO-4-ACYLAMINO-5(3)-ARYLSULFANYLPYRAZOLES
1819
C32
C33
C31
C30
C29
C28
C4
O2
C10
N1
N2
C5
C9
S1
C27
C8
C1
C26
C3
C6
C2
C11
C12
C13
N3
C7
C16
N4
C15
C13
C18
O1
C24
C19
C23
C20
C17
C21
C22
C25
Structure of the molecule of 6,6-dimethyl-8-oxo-9-phenyl-3-p-toluoylamino-2-p-tolylsulfanyl-4,5,6,7,8,9-hexahydropyrazolo-
[5,1-b]quinazoline (VIIId) according to the X-ray diffraction data (hydrogen atoms are not shown).
Enraf Nonius CAD-4 four-circle automatic diffrac-
tometer (CuK irradiation, 1.54178 ; scan rate
ratio 2 / = 1.2, = 69 , spherical segment 0
30.0
13.0 malx 26). Total of 6583 reflections
from geometry considerations. All hydrogen atoms
were included in the refinement procedure with fixed
positional and thermal parameters; only the positions
of H3 and H4 were refined in isotropic approximation.
The Chebyshev weight scheme [11] with five param-
eters (1.36, 0.77, 0.60, 0.64, and 0.07) was used in
the refinement. The final divergence factors were R
0.058 and RW 0.062, GOF = 1.119. The residual
electron density from the Fourier difference series
was 0.38 and 0.23 e/ 3. The absorption by the
crystal was taken into account by azimuthal scanning
[12]. The complete set of crystallographic data
for compound VIIId was deposited to the Cam-
bridge Crystallographic Data Center (entry no.
CCDC 244185).
h
k
were measured. Rhombic crystals with the following
unit cell parameters: a 25.122(3), b 12.193(4), c
21.480(6) ; V 6580(3) 3; M 593.8; Z 8;
=
calc
3
1
1.20 g cm ; = 11.8 cm ; F(000) = 2520.0; space
group Pbcn (N 60). The structure was solved by the
direct method and was refined by the least-squares
procedure in full-matrix anisotropic approximation
using CRYSTALS software package [10]. The struc-
ture was refined on the basis of 2993 reflections with
I > 3 (I) (396 refined parameters, 7.6 reflections per
parameter); 50% of hydrogen atoms were visualized
by the difference synthesis of electron density, and
positions of the other hydrogen atoms were calculated
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 11 2005

1820
POPIL’NICHENKO et al.
3-Arylsulfanyl-2-acylamino-3-chloroacrylonit-
riles IIIa IIIc were synthesized according to the
procedure described in [3] for compound IIIa.
was heated for 5 h at the boiling point. The mixture
was cooled and diluted with 20 ml of isopropyl al-
cohol, and the precipitate was filtered off and recrys-
tallized from ethanol.
3(5)-Amino-5(3)-arylsulfanyl-4-acylaminopyra-
zoles IVa IVc (general procedure). Hydrazine hyd-
rate, 0.025 mol, was added to a solution of 0.01 mol
of compound IIIa IIIc in 30 ml of ethanol, and the
mixture was heated for 4 h under reflux. Volatile
substances were removed under reduced pressure, the
residue was treated with water, and the precipitate was
filtered off and recrystallized from appropriate solvent.
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(Syntheses of Nitrogen-Containing Heterocyclic
Compounds on the Basis of Amidoalkylating Agents),
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2-Arylsulfanyl-3-acylamino-5,7-dimethylamino-
pyrazolo[1,5-a]pyrimidines Va Vc (general pro-
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solution of 0.02 mol of compound IVa IVc in 30 ml
of toluene, and the mixture was heated for 10 h under
reflux. Most part of the solvent was removed under
reduced pressure, and the precipitate was filtered off
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tuted pyrazole IVa IVc and 0.1 mol of ethyl aceto-
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VIIb (general procedure). A mixture of 0.01 mol of
compound IVa or IVb, 0.1 mol of ethyl acetoacetate,
and 0.02 mol of triethylamine was heated for 5 h at
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9-Aryl-3-acylamino-6,6-dimethyl-8-oxo-2-p-tolyl-
sulfanyl-4,5,6,7,8,9-hexahydropyrazolo[5,1-b]-
quinazolines VIIIa, VIIIb, and VIIId (general
procedure). A mixture of 0.01 mol of compound IVa
or IVb, 0.01 mol of dimedone, and 0.01 mol of benz-
aldehyde or p-chlorobenzaldehyde in 5 ml of DMF
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RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 11 2005