Synthesis and structural determination of 5-arylamino-1,3-dimethylpyrazoles

Article abstract of DOI:10.1007/s10593-005-0115-6

Treatment of 4-arylamino-4-thioxo-2-butanones with methylhydrazine in acetic acid gives 5-arylamino-1,3-dimethylpyrazoles which are readily halogenated in the 4 position. The thermal decomposition of 3-anilino-1,2,5- trimethyl-1H-pyrazolium chloride gives

Full text of DOI:10.1007/s10593-005-0115-6

Chemistry of Heterocyclic Compounds, Vol. 41, No. 1, 2005
SYNTHESIS AND STRUCTURAL
DETERMINATION OF 5-ARYLAMINO-
1,3-DIMETHYLPYRAZOLES
V. N. Britsun, I. M. Bazavova, V. N. Bodnar, A. N. Chernega, and M. O. Lozinskii
Treatment of 4-arylamino-4-thioxo-2-butanones with methylhydrazine in acetic acid gives 5-arylamino-
1,3-dimethylpyrazoles which are readily halogenated in the 4 position. The thermal decomposition of
3-anilino-1,2,5-trimethyl-1H-pyrazolium chloride gives 1,3-dimethyl-5-phenylaminopyrazole and
1,5-dimethyl-3-phenylaminopyrazole in the approximate ratio of 1: 1.
Keywords: 4-arylamino-4-thioxo-2-butanone, 5-arylamino-1,3-dimethylpyrazoles, 1,5-dimethyl-3-
phenylaminopyrazole, methylhydrazine.
Alkyl-5-arylaminopyrazoles are promising materials for pharmacological study [1], e.g. they can be used
as antiallergic or antipyretic agents [2, 3]. More recently, the use of alkyl 5-arylaminopyrazoles as potential
pesticides has been noted [4-6]. However, the simplest representatives of the 5-arylamino-1,3-dimethyl-
pyrazoles and 5-arylamino-1,5-dimethylpyrazoles are virtually unknown in the literature with the exception of a
study [7] in which the decomposition of a quaternary pyrazolium salt gave 1,3-dimethyl-5-
phenylaminopyrazole.
It has previously been shown that 4-anilino-4-thioxo-2-butanones react with hydrazine to give
5-arylamino-3-methylpyrazoles [8, 9]. With the aim of preparing dialkylarylaminopyrazoles we now report the
reaction of the 4-arylamino-4-thioxo-2-butanones 1a-c with methylhydrazine in acetic acid. In this way both
5-arylamino-1,3-dimethylpyrazoles 2 and 3-arylamino-1,5-dimethylpyrazoles 3 may be formed.
Br
Me
Me
N
NH–Ar
4a–c
N
N
Me
Me
Me
NH–Ar
NH–Ar
N
3
Me–NH–NH2
–H2O, –H2S
Me–C–CH2–C–NH–Ar
Br2/MeCOOH
Me
O
S
1
Cl
SO2Cl2
N
N
N
NH–Ar
N
Me
2a–c
Me
5a,b
1-5 а Ar = Ph, b Ar = p-ClC6H4; 2, 4 c Ar = p-BrC6H4
__________________________________________________________________________________________
Institute of Organic Chemistry, Ukraine National Academy of Sciences, Kiev 02094, e-mail:
iochkiev@ukrpack.net. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 120-126, January,
2005. Original article submitted December 30, 2002.
0009-3122/05/4101-0105©2005 Springer Science+Business Media, Inc.
105

According to 1H NMR spectroscopic data the reaction occurs in one way. The yields, melting points, and
1
elemental analytical data for the compounds synthesized are given in Table 1 and the H NMR spectroscopic
1
data in Table 2. In the H NMR spectra of the compounds prepared there are present signals for the NH groups
(7.89-8.48), aromatic ring protons (6.75-7.41) and pyrazole ring protons (5.77-5.93 ppm). It should be noted that
it is impossible to determine which of the isomers 2 or 3 is formed on the basis of the 1H NMR data. According
to the data in [8] the formation of compounds 2a-c is more likely, however the melting point of the compound
synthesized by us from 4-anilino-4-thioxo-2-butanone (148-150°C) is markedly different to the melting point
reported in [7] for 1,3-dimethyl-5-phenylaminopyrazole (95°C). Hence an identification was made for the
compound using X-ray structural analysis and it was found that it is 1,3-dimethyl-5-phenylaminopyrazole (2a)
(see Fig. 1 and Table 3).
TABLE 1. Parameters for Compounds 2-5 and 7-9
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Yield,
%
mp, °С
С
H
N
2a
2b
2c
3a
4a
4b
4с
5a
5b
7
C11H13N3
70.71
70.56
59.44
59.60
49.78
49.64
70.49
70.56
49.48
49.64
43.61
43.95
38.58
38.29
59.83
59.60
51.44
51.58
43.83
43.78
71.53
71.61
60.48
60.63
6.88
7.00
5.58
5.46
4.81
4.54
6.74
7.00
4.69
4.54
3.39
3.69
3.46
3.21
5.23
5.46
4.40
4.33
5.16
4.90
7.64
7.51
6.56
6.78
22.10
22.44
19.10
18.95
15.71
15.79
22.34
22.44
15.60
15.79
13.74
13.98
12.04
12.18
18.71
18.95
16.68
16.41
12.89
12.76
20.95
20.88
17.83
17.68
148-150
95-97
86
67
73
21
70
62
64
58
65
68
77
85
C11H12ClN3
C11H12BrN3
C11H13N3
120-122
115-117
105-107
115-117
129-30
108-110
93-95
C11H12BrN3
C11H11BrClN3
C11H11Br2N3
C11H12ClN3
C11H11Cl2N3
С12Н16IN3
184-186
80-82
8
С12Н15N3
9
С12Н16ClN3
238-240
Fig. 1. Overall view of the molecule of 2a with atom numbering.
106

TABLE 2. 1H NMR Spectra of Compounds 2-5 and 7-9
Com-
pound
Chemical shifts (DMSO-d6), δ, ppm (J, Hz)
2a
2b
2c
3а
2.09 (3Н, s, СН3-3); 3.55 (3Н, s, СН3-1); 5.77 (1Н, s, H-4 pyrazole);
6.75-7.18 (5Н, m, С6Н5); 7.88 (1Н, s, NН)
2.16 (3Н, s, СН3-3); 3.09 (3Н, s, СН3-1); 5.91 (1Н, s, H-4 pyrazole);
6.95 (2Н, d, J = 10.1, o-НAr); 7.28 (2Н, d, J = 10.1, m-НAr); 8.45 (1Н, s, NН)
2.16 (3Н, s, СН3-3); 3.61 (3Н, s, СН3-1); 5.93 (1Н, s, H-4 pyrazole);
6.87 (2Н, d, J = 11.0, o-НAr); 7.41 (2Н, d, J = 11.0, m-НAr); 8.48 (1Н, s, NН)
2.19 (3H, s, CH3-5); 3.60 (3H, s, CH3-1); 5.60 (1H, s, H-4 pyrazole);
6.67-7.28 (5H, m, С6Н5); 8.26 (1H, s, NH)
4a
4b
2.14 (3H, s, CH3-3); 3.58 (3H, s, CH3-1); 6.52-7.15 (5Н, m, С6Н5); 7.89 (1H, s, NH)
2.12 (3H, s, CH3-3); 3.56 (3H, s, CH3-1); 6.56 (2Н, d, J = 9.7, o-HAr);
7.20 (2Н, d, J = 9.7, m-HAr); 8.09 (1H, s, NH)
4c
2.13 (3H, s, CH3-3); 3.56 (3H, s, CH3-1); 6.47 (2Н, d, J = 9.2, o-HAr);
7.30 (2Н, d, J = 9.2, m-HAr); 8.14 (1H, s, NH)
5a
5b
2.13 (3H, s, CH3-3); 3.56 (3H, s, СH3-1); 6.54-7.13 (5Н, m, С6Н5); 7.95 (1H, s, NH)
2.12 (3H, s, CH3-3); 3.55 (3H, s, CH3-1); 6.55 (2Н, d, J = 10.1, o-HAr);
7.21 (2Н, d, J = 10.1, m-HAr); 8.15 (1H, s, NH)
7
8
9
2.37 (3H, s, CH3-5); 3.79 (3H, s, CH3-1); 3.88 (3H, s, CH3-2); 6.27 (1H, s, H-4 pyrazole);
7.08-7.39 (5Н, m, С6Н5); 9.23 (1Н, s, NH)
2.08 (3H, s, CH3-5); 3.20 (3H, s, CH3-1); 3.25 (3H, s, CH3-2); 5.52 (1H, s, H-4 pyrazole);
6.65-7.16 (5Н, m, С6Н5)
2.36 (3H, s, CH3-5); 3.76 (3H, s, CH3-1); 3.98 (3H, s, CH3-2); 6.26 (1H, s, H-4 pyrazole);
7.10-7.38 (5Н, m, С6Н5); 10.05 (1Н, s, NH)
The pyrazole ring N(1)N(2)C(1)C(2)C(3) is planar with a deviation of the atoms from the mean square plane
not greater than 0.007 Å. The geometrical parameters of this ring point to a significant delocalization of the
electron density and this is quite typical for analogous systems. The C(3)N(3)C(6-11) grouping is planar within the
limits 0.020 Å and forms a dihedral angle of 76.2° with the five membered ring. The N(2) and N(3) atoms have,
respectively, planar trigonal and slightly pyramidal configured bonds with overall valence angles of 359.9 and
350.8°. Via N(3)–H(3)···N(1) intramolecular hydrogen bonds with mean values of N(3)···N(1) 3.00(6), N(1)···H(3)
2.10 (6), N(3)–H(3) 0.90(6) Å, and N(3)H(3)N(1) 174(3)° the molecules of 2a are combined in the crystal through
infinite chains (Fig. 2).
Fig. 2. Crystal packing of compound 2a (intermolecular hydrogen bonds indicated by dotted lines).
107

TABLE 3. Interatomic Distances (d) and Valence Angles (ω) in the
Molecule of Compound 2a
Bond
d, Å
Angle
ω, deg.
N(1)–N(2)
N(1)–C(1)
N(2)–C(3)
N(2)–C(5)
N(3)–C(3)
N(3)–C(6)
C(1)–C(2)
C(1)–C(4)
C(2)–C(3)
1.361(6)
1.328(6)
1.339(6)
1.454(6)
1.395(7)
1.418(7)
1.403(7)
1.481(8)
1.371(7)
N(2)–N(1)–C(1)
N(1)–N(2)–C(3)
N(1)–N(2)–C(5)
C(3)–N(2)–C(5)
C(3)–N(3)–C(6)
N(1)–C(1)–C(2)
C(1)–C(2)–C(3)
N(2)–C(3)–C(2)
104.7(4)
112.0(4)
120.1(4)
127.8(4)
120.5(5)
111.1(4)
105.0(4)
107.1(4)
Since the 5-arylamino-1,3-dimethylpyrazoles 2a-c are little studied we have carried out their
chlorination (sulfuryl chloride in benzene) and bromination (a solution of bromine in acetic acid). When
compared with the spectra of the starting compounds 2a-c, the 1H NMR spectra of the halogenation products (4,
5) show the absence of the signal for the pyrazole ring proton (a singlet in the range 5.77-5.93 ppm).
In order to clear up the structure of the compound which, according to [7], is a result of the
decomposition of the quaternary salt 9 we have carried out a series of reactions. The pyrazole 2a was treated
with dimethylsulfate to give the 5-anilino-1,2,3-trimethyl-1H-pyrazolium methylsulfate 6.
Compound 6 was treated with a solution of sodium hydroxide to give the imine 8 which was then treated
with gaseous HCl in dry ether to give the pyrazolium chloride 9. The quaternary salt 9 was decomposed as
reported in the method [7]. The melting point of the compound sythesized in this way was 94-95° which
1
corresponded to the data in [7]. Using H NMR spectroscopy it was shown that the result of the thermal
decomposition of compound 9 is not the 1,3-dimethyl-5-phenylaminopyrazole 2a as indicated in [7] but a
mixture with the isomeric 1,5-dimethyl-3-phenylaminopyrazole 3a in the approximate ratio 1:1.
This formation of an equal amount of the two isomeric pyrazoles 2a and 3a points to an approximately
equal localization of the positive charge on both nitrogen atoms of the pyrazole ring in the pyrazolium
chloride 9.
Me
Me
KI
Me2SO4
+
MeCOONa
+
N
N
2a
Me
NH–Ph
Me
NH–Ph
_
N
N
_
I
Me
Me
MeSO4
6
7
Me
Me
Me
N
200 oC
–MeCl
HCl
+
N
2a
3a
+
NH–Ph
_
Me
N–Ph
N
N
Me Cl
Me
8
9
108

The 1H NMR spectrum of the 1,5-dimethyl-3-phenylaminopyrazole 3a differs slightly from the 1H NMR
spectrum of 1,3-dimethyl-5-phenylaminopyrazole 2a in that the signal of the pyrazole ring proton in compound
3a is shifted by 0.17 ppm to high field and that of the NH group by 0.38 ppm to low field of the analogous
proton signals in the isomeric compound 2a. Evidently this is associated with the fact that , in the pyrazole 3a,
the two methyl groups situated in the 1 and 5 positions of the pyrazole ring slightly polarize the molecule of 3a
when compared with the isomeric pyrazole 2a.
EXPERIMENTAL
1H NMR spectra were recorded on a Varian-300 instrument (300 MHz) using TMS as internal standard.
4-Arylamino-4-thioxo-2-butanones were prepared as in method [8].
5-Arylamino-1,3-dimethylpyrazoles 2a-c. A solution of methylhydrazine (0.012 mol) in water (10 ml)
was added to a solution of the 4-arylamino-4-thioxo-2-butanone 1 (0.01 mol) in acetic acid (40 ml) at 20°C and
left for 24 h. The reaction product was diluted with cold water (100 ml) and filtered. A saturated solution of
sodium acetate (50 ml) was added to the filtrate and left for 5 h at 4°C. The precipitated crystals of 2a-c were
filtered off, dried, and recrystallized from aqueous alcohol (1:1).
X-ray Structural Investigation of Compound 2a. Crystals of compound 2a are monoclinic with
a = 11.187(7), b = 7.826(4), c = 11.876(9) Å; β = 102.111(7)°; V = 1016.6 Å3; Z = 4; M = 187.25;
d = 1.22 g/cm3; space group P21/c; µ = 0.71, F(000) = 400, crystal size 0.25 × 0.41 × 0.47 mm. Crystallographic
measurements were carried out on an Enraf-Nonius CAD-4, four circle, automatic diffractometer at 18°C
(MoKα radiation, λ = 0.71069 Å. relative scanning rate ω/2θ = 1.2, 2 < θ <25°, spherical segment 0 < h <12, 0 <
k <8, -13 < l <13). In all, 1836 reflections were collected, of which 1597 were symmetrically independent with
Rint = 0.035. The structure was solved by a direct method using least squares refinement in a full matrix,
anisotropic approximation using the CRYSTALS [10] program package. 710 Reflections were used in the
refinement with I < 4σI (131 refinement parameters, number of reflections per parameter 5.5). All of the
hydrogen atoms were revealed in the electron density difference synthesis and included in the refinement with
fixed positions and thermal parameters (only atom H(3), which takes part in the formation of an intramolecular
bond, was refined isotropically). Calculation of the absorption in the crystal was carried out using the azimuthal
scanning method [11]. In the refinement the Chebyshev weighting scheme [12] was used with five parameters:
0.85, -0.10, 0.60, -0.17, and 0.14. The final difference factor values were R = 0.058 and Rw = 0.065,
GOF = 1.207. The residual electron density from the Fourier difference series 0.25 and -0.25 e/Å3. Atomic
coordinates are given in Table 2. The full set of crystallographic data has been deposited with the Cambridge
structural data bank (register No CCDC 176864).
5-Arylamino-4-bromo-1,3-dimethylpyrazoles 4a-c. A solution of bromine (0.01 mol) in acetic acid
(10 ml) was added to a solution of compound 2 (0.01 mol) in acetic acid (20 ml) at 20°C. After stirring for 4 h,
the reaction product was diluted with a saturated solution of sodium acetate (40 ml). The precipitated product 4a-
c was filtered, dried, and recrystallized from ethanol.
5-Arylamino-1,3-dimethyl-4-chloropyrazoles 5a,b. A solution of sulfuryl chloride (0.01 mol) in
benzene (10 ml) was added to a solution of compound 2a,b (0.01 mol) in benzene (20 ml). After stirring for 6 h,
the reaction product was washed with a solution of sodium acetate, dried over magnesium sulphate, and
evaporated using a water pump vacuum. The Crystals of 5a,b were recrystallized from ethanol.
3-Anilino-1,2,5-trimethyl-1H-pyrazolium iodide (7). A mixture of the pyrazole 2a (0.01 mol) and
dimethylsulfate (0.02 mol) was heated at 150°C for 10 min, cooled, water (5 ml) was added, and the product was
heated until solution was complete. The reaction mixture was then treated with a saturated solution of aqueous
KI. The precipitated solid 7 was filtered off, washed with ethanol (2 × 5 ml), and dried.
109

1,2,5-Trimethyl-3-phenylimino-2,3-dihydropyrazole (8). A mixture of the pyrazole 2a (0.05 mol) and
dimethylsulfate (0.1 mol) was heated at 150°C for 10 min, cooled, treated with a 20% solution of sodium
hydroxide to a strongly basic reaction, and extracted with diethylether (2 × 20 ml). The combined ether extracts
were dried over magnesium sulphate and the ether was evaporated off using a water pump vacuum. Standing at
4°C gave 8 as colorless crystals with a characteristic smell.
3-Anilino-1,2,5-trimethyl-1H-pyrazolium chloride (9). A current of dry hydrogen chloride was passed
through a solution of compound 8 (0.01 mol) in ether (30 ml) at 20°C for 20 min. The reaction product 9 was
separated as a rapidly solidifying oil. It was held for 2 h at 4°C, filtered, and washed with ether (2 × 10 ml).
Dehaloalkylation of compound 9. The chloride 9 (0.01 mol) was heated in a water pump vacuum at
200°C. Gases were evolved and the reaction products were sublimed and deposited on the cooled walls of a flask
as a rapidly solidifying oil. Crystallization of the reaction product from hexane gave needles with mp 94-95°C.
Fractional crystallization from hexane gave the 1,5-dimethyl-3-phenylaminopyrazole 3a.
The authors thank the firm Aventis (Germany) for financial support of the investigation.
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