Conditions for the selective conversion of quaternary 3-anilino-1,5- dimethylpyrazolium salts into 3-anilino-1,5-dimethylpyrazole

Article abstract of DOI:10.1023/B:COHC.0000037311.01960.3e

The possibility has been studied of converting quaternary 3-anilino-1,5-dimethylpyrazolium salts into 3-anilino-1,5-dimethylpyrazole, the first representative of the 1-alkyl-3-arylaminopyrazoles. The dependence of the reaction direction on the nature of the substituent at position 2 has been clarified. The most effective result was obtained with a cyanoethyl substituent. On boiling the initial salt with aqueous ammonia the target product is isolated in quantitative yield. Syntheses of the initial salts are described. C-Sulfonation was detected on interacting 3-anilino-1-benzoyl-3-methylpyrazole and dimethyl sulfate, with the formation of p-(3-amino-1,2,5-trimethylpyrazolio) benzenesulfonate.

Full text of DOI:10.1023/B:COHC.0000037311.01960.3e

Chemistry of Heterocyclic Compounds, Vol. 40, No. 5, 2004
CONDITIONS FOR THE SELECTIVE
CONVERSION OF QUATERNARY 3-ANILINO-
1,5-DIMETHYLPYRAZOLIUM SALTS INTO
3-ANILINO-1,5-DIMETHYLPYRAZOLE
I. B. Dzvinchuk1, S. A. Kartashov1, A. V. Vypirailenko1, U. Doller2, and M. O. Lozinskii1
The possibility has been studied of converting quaternary 3-anilino-1,5-dimethylpyrazolium salts into
3-anilino-1,5-dimethylpyrazole, the first representative of the 1-alkyl-3-arylaminopyrazoles. The
dependence of the reaction direction on the nature of the substituent at position 2 has been clarified. The
most effective result was obtained with a cyanoethyl substituent. On boiling the initial salt with aqueous
ammonia the target product is isolated in quantitative yield. Syntheses of the initial salts are described.
C-Sulfonation was detected on interacting 3-anilino-1-benzoyl-3-methylpyrazole and dimethyl sulfate,
with the formation of p-(3-amino-1,2,5-trimethylpyrazolio)benzenesulfonate.
Keywords: hydrazines, pyrazoles, dehaloalkylation, quaternization, selectivity, C-sulfonation,
cyanoethylation.
Arylamino-substituted pyrazoles have been known for more than a hundred years [1]. Up to the present
time efficient pesticides [2], antipyretics [3], disperse dyestuffs [4], and anti-inflammatory [5] and hypotensive
[6] agents have appeared among their derivatives. However 1-alkyl-3-arylaminopyrazoles have not been
described until now. Their synthesis is expedient for the search for new substances of practical use, but
problematical from a methodological point of view. In particular, according to the data of the Michaelis school
[7-9], on thermal dehalogenalkylation of quaternary 3-arylaminopyrazolium salts the alkyl group bound to the
ring nitrogen atom in position 1 is split off and 5-arylaminopyrazoles are formed. We assumed that this reaction
may be converted into a method of synthesizing 3-arylaminopyrazoles. A necessary condition must probably be
the presence of a readily leaving substituent in position 1 of the initial salts. Experimental verification of the
hypothesis and selection of a suitable substituent has been carried out on quaternary 3-anilino-1,5-
dimethylpyrazolium salts and is presented in this work.
First we contemplated synthesizing and testing quaternary pyrazolium salts containing such readily
leaving groups as benzoyl in position 1. The interaction of acetothioacetanilide (1) and benzoylhydrazine (2a)
with the formation of the initial 5-anilino-1-benzoylpyrazole (3a) has been described by us previously [10].
Quaternization of compound 3a with dimethyl sulfate proceeds, as we found, ambiguously and did not stop at
the stage of forming the expected quaternary salt 4a. The subsequent conversion is probably effected through a
series of intermediate compounds 5-7. After treatment of the reaction mixture with aqueous ammonia a
compound with a betaine structure 8 was obtained in low yield. The result indicates that the benzoyl group is
__________________________________________________________________________________________
1
Institute of Organic Chemistry, National Academy of Sciences of the Ukraine, Kiev 02094; e-mail:
2
iochkiev@ukrpack.net. Aventis CropScience Gmbh, D-65926, Frankfurt-on-Main, Germany. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, Vol. 40, No. 5, pp. 679-684, May, 2004. Original article submitted
November 19, 2001.
570
0009-3122/04/4005-0570©2004 Plenum Publishing Corporation

unsuitable for the solution of the problem being investigated. It leaves the nitrogen atom even under the
conditions for obtaining the initial salt under the action of the nascent, low reactivity nucleophile, methylsulfate
anion. Probably a mixed anhydride of methyl sulfate and benzoic acid is formed, which then sulfonates the
aniline fragment at the para position. The possibility also appears of methylating the second ring nitrogen atom,
which has been carried out.
Me
NHPh
MeCOCH2CSNHPh
1
3b
N
N
+
NH2NHR
2a–c
Me
–EtI, –MeI
NHPh
R = Et: 170 oC
5
Me
Me
NHPh
R
R = Et, (CH2)2CN
MeI
+
N
N
N
N
Me
R
_
I
3a–c
4b,c
R = (CH2)2CN: H2O,
NH4OH
5
∆ , 2–3 min, –NH4I,
–H2N(CH2)2CN
Me
NHPh
R = COPh: Me2SO4
120 oC, 5 h
+
N
N
–MeOSO2OCOPh
Me
R
_
MeOSO3
4a
Me
NHPh
MeOSO2OCOPh
–PhCOOH
Me2SO4
+
5
N
N
Me
Me
_
MeOSO3
6
H
Me
N
SO3Me
H2O, NH4OH
+
N
N
Me
Me
_
MeOSO3
7
_
SO3
H
Me
N
+
N
N
Me
Me
8
2– 4 a R = COPh, b R = Et, c R = (CH2)2CN
571

Proceeding from the results presented it was necessary to test more stable substituents. Ethyl and
cyanoethyl were tested. By interacting reactant 1 with ethyl- and cyanoethylhydrazines 2b,c by the procedure of
[11] we obtained the corresponding previously undescribed pyrazoles 3b,c. These compounds were more
nucleophilic than the N-benzoyl analog 3a mentioned above. Quaternization took place under the action of an
excess of methyl iodide on extended refluxing in acetone and gave the starting salts 4b,c in high yield.
The ethyl-substituted salt 4b underwent dehaloalkylation on refluxing in diglyme. However the process
occurred nonselectively with fission of ethyl and methyl iodides. As was established by 1H NMR, a mixture was
formed of the desired compound 5 and the ethylpyrazole 3b mentioned already in a molar ratio of 2:3. The
mixture was not successfully separated either by crystallization or chromatographically (compounds 4c and 5
have practically coincident Rf values).
As we revealed, the cyanoethyl group possesses optimal properties for an efficient solution to the
problem being investigated. In difference to benzoyl it was retained on obtaining the quaternary salt, and, in
difference to ethyl, was readily removed from the salt regioselectively. The reaction occurred on boiling salt 4c
in aqueous ammonia and was complete after 2-3 min. The conversion is probably fission of hydriodic acid and
transcyanoethylation. Ammonium iodide and 3-aminopropionitrile, the formation of which must be expected, are
soluble in water and do not impede the isolation of the desired product. Compound 5 crystallized from the
reaction mixture in practically quantitative yield in an analytically pure state.
The compounds 3b,c, 4b,c, 5, and 8 synthesized by us were colorless crystalline substances. Salts 4b,c
and 8 were soluble in hot water, poorly in cold, and in acetone. The remaining compounds were soluble in
acetone, chloroform, and ethyl acetate, worse in alcohol (with the exception of product 5), and insoluble in
hexane and water. On extended storage iodides 4b,c acquire a yellow color, but the remaining compounds were
unchanged.
Pyrazoles 3b,c and salts 4b,c were obtained by us by standard methods and their structures were
confirmed by the investigations carried out. The formation of betaine 8 was unexpected. This is the first
example known to us of C-sulfonation on interaction with dimethyl sulfate. Nonetheless the structure of 8
followed readily from the data of 1H NMR spectra. The chemical shifts of the Н-4 proton, and of the protons of
the methyl and amino groups linked to the heterocycle were extremely close in size to those detected for the
quaternary salts 4b,c. The appearance of the aromatic protons of the aniline fragment was typical for a
1
1,4-disubstituted benzene ring. Comparison of the H NMR spectra of 3-arylaminopyrazole 5 and 5-arylamino-
pyrazoles 3b,c clearly indicates the energetically more favorable conjugation system between the nitrogen atom
of the aniline fragment and the ring C=N bond in the first compound. This is caused by the fact that the
conjugation system is one multiple bond shorter. As a result the electron density is increased at the heterocycle
and reduced at the extracyclic amino group. The signal of the H-4 proton of compound 5 was displaced by
0.16-0.20 ppm towards high field, but the amino group proton was displaced by 0.29-0.47 ppm towards low
field. The appearance of the aromatic protons of the aniline fragment was extremely noteworthy. In compounds
3b,c and the quaternary salts 4b,c the extracyclic nitrogen atom exerts an electron-donating influence on the
phenyl fragment, and the signals of its protons appeared in the sequence m, o, and p from low to high field. For
compound 5 the sequence of the o- and p-signals was different going towards high field and the signal of the
o-protons was displaced (compared with compounds 3b,c) by 0.40-0.50 ppm towards low field. The effect is
probably caused by the deshielding effect of the lone pair of electrons of the pyrazole nitrogen atom.
Deshielding of the aniline fragment is of course possible only for structure 5 as it exerts maximum effect on the
spatially closely disposed o-protons.
The selective N-decyanoethylation of pyrazolium salts, shown by us, probably has a general character.
In view of the availability of cyanoethylhydrazine [12] this reaction may be used for the directed synthesis of
new 1-alkyl-3-arylaminopyrazoles. It is also expedient to study the N-decyanoethylation of a series of 1,2- and
1,3-diazolium salts as a method of synthesis of previously unknown or difficultly available compounds.
572

TABLE 1. Physicochemical and Spectral Characteristics of Compounds
3b,c, 4b,c, 5, and 8
Found, %
——————
Calculated, %
IR spectrum,
Com-
pound
Empirical
formula
mp, °C*
Yield %
ν, cm-1
С
Н
N
3b
3c
C12H15N3
71.45
71.61
69.16
69.00
7.56
7.51
6.14
6.24
20.81
20.88
24.60
24.76
113-114
3210 (NH)
67
75
C13H14N4
121-121.5
2255 (C≡N),
3240 (NH)
4b
4c
C13H18IN3
C14H17IN4
45.55
45.49
45.61
45.66
5.27
5.29
4.58
4.65
12.18
12.24
15.18
15.22
135-136
201-202
3225 (NH)
98
97
2260 (C≡N),
3110 (NH)
5
8
C11H13N3
70.39
70.56
51.29
51.23
7.07
7.00
5.45
5.37
22.40
22.44
14.79
14.94
101-103
345-347
3250 (NH)
97
38
C12H15N3O3S*2
3215, 3490
(NH)
_______
* Compounds were crystallized from 2-propanol (3c, 4b), water–2-propanol,
1:2 (3b, 4c), hexane–ethyl acetate,
4:1 (5), water–acetic acid, 4:1 (8).
*2 Found, %: S 11.49. Calculated, %: S 11.40.
TABLE 2. 1H NMR Spectra of Compounds 3b,c, 4b,c, 5, and 8
Com-
pound
Chemical shifts (DMSO-d6), δ, ppm (J, Hz)
3b
1.24 (3H, t, J = 7.2, СН3CH2); 2.11 (3H, s, СН3Het); 3.89 (2H, q, J = 7.2, СН2CH3);
5.76 (1H, s, Н-4); 6.73 (1H, t, J = 7.2, p-ptoton С6Н5);
6.79 (2H, d, J = 7.8, o-protons С6Н5); 7.16 (2H, dd, J1 = 7.2, J2 = 7.8, m-protons С6Н5);
7.78 (1H, s, NH)
3c
4b
4c
2.12 (3H, s, СН3Het), 2.96 (2H, t, J = 6.3, CH2CN), 4.15 (2H, t, J = 6.3, СН2N),
5.81 (1H, s, Н-4), 6.78 (1H, t, J = 7.5, p-ptoton С6Н5), 6.88 (2H, d,
J = 7.8, o-protons С6Н5), 7.19 (2H, dd, J1=7.2, J2 = 7.8, m-protons С6Н5), 7.96 (1H, s, NH)
1.29 (3H, t, J = 6.9, СН3CH2), 2.37 (3H, s, СН3Het), 3.84 (3H, s, CH3N), 4.42 (2H, q,
J = 6.9, СН2CH3), 6.25 (1H, s, Н-4), 7.14 (1H, t, J = 6.9, p-ptoton С6Н5), 7.26 (2H, d,
J = 7.5, o-protons С6Н5), 7.41 (2H, dd, J1=6.9, J2 = 7.5, m-protons С6Н5), 9.26 (1H, s, NH)
2.37 (3H, s, СН3Het), 3.11 (2H, t, J = 6.9, CH2CN), 3.84 (3H, s, CH3N), 4.74 (2H, t,
J = 6.9, СН2N), 6.27 (1H, s, Н-4), 7.15 (1H, t, J = 7.6, p-ptoton С6Н5), 7.26 (2H, d,
J = 7.8, o-protons С6Н5), 7.43 (2H, dd, J1 = 7.6, J2 = 7.8, m-protons С6Н5),
9.47 (1H, s, NH)
5
8
2.18 (3H, s, СН3Het), 3.60 (3H, s, CH3N), 5.60 (1H, s, Н-4), 6.67 (1H, t,
J = 7.2, p-ptoton С6Н5), 7.14 (2H, dd, J1 = 7.2, J2 = 7.5, m-protons С6Н5), 7.29 (2H, d,
J = 7.5, o-protons С6Н5), 8.25 (1H, s, NH)
2.36 (3H, s, СН3Het), 3.79 (3H, s, CH3N), 3.83 (3H, s, CH3N), 6.30 (1H, s, Н-4),
7.08, 7.60 (4H, dd, J = 8.4, p-С6Н4), 9.31 (1H, s, NH)
EXPERIMENTAL
The IR spectra were recorded on a UR 20 instrument in KBr disks. The 1H NMR spectra were recorded
on a Varian VXR 300 (300 MHz) spectrometer, internal standard was TMS. A check on the progress of reactions
and the homogeneity of the compounds synthesized was effected by TLC on Silufol UV 254 plates in the solvent
system benzene–ethanol, 9:1 (visualization in UV light).
The characteristics of the synthesized compounds are given in Tables 1 and 2.
573

1-Substituted 5-Anilino-3-methylpyrazoles (3b,c). A solution of hydrazine 2b or 2c (12 mmol) in
2-propanol (2 ml) was added dropwise during 5 min to a boiling solution of compound 1 (1.93 g, 10 mmol) in
2-propanol (3 ml). Boiling was continued for a further 15 min to complete the reaction. The mixture was stirred
until crystallization commenced (in the synthesis of compound 3b the reaction mixture was first diluted with
water (5 ml)), then maintained at 15-20°C for 2 h, and at -5°C for 1 h. The solid was filtered off, and washed
with aqueous 2-propanol, 1:1.
2-Substituted 3-Anilino-1,5-dimethylpyrazolium Iodides (4b,c). Mixtures of pyrazole 3b or 3c
(3 mmol), methyl iodide (4.43 g, 30 mmol), and acetone (1.5 ml) were refluxed for 9 or 45 h respectively. After
cooling, the solid was filtered off, and washed with acetone. Compound 4b was recrystallized from 2-propanol.
Compound 4c was obtained in an analytically pure state.
3-Anilino-1,5-dimethylpyrazole (5). A mixture of salt 4c (0.74 g, 2 mmol) and 20% aqueous ammonia
(2 ml) was stirred and refluxed for 2-3 min. Water (2 ml) was then added and the mixture stirred until the
resulting oil crystallized. After cooling, the solid was pulverized, filtered off, washed with water, and dried at 80°C.
p-(3-Amino-1,2,5-trimethylpyrazolio)benzenesulfonate (8). A mixture of pyrazole 3a (1.38 g,
5 mmol) and freshly distilled dimethyl sulfate (1.51 g, 12 mmol) was maintained at 115-120°C for 5 h. After
cooling, water (3 ml) and 20% aqueous ammonia (3 ml) were added. The mixture was stirred and refluxed for
2-3 min. After cooling, the solid was filtered off, washed with water, with 2-propanol, and with ether.
Dehaloalkylation of 3-Anilino-2-ethyl-1,5-dimethylpyrazolium Iodide. Compound 4b (0.2 g) was
refluxed in diglyme (1 ml) for 8 h. The solvent was evaporated in the vacuum of a water-jet pump with heating
on a boiling water bath. The residue was dissolved in methylene chloride (5 ml) and passed through a column of
Al2O3 (d = 1 cm, h = 4 cm), eluting with methylene chloride, and discarding eluate in front of the running
colorless fraction. The solvent was evaporated. The residue was dried from traces of diglyme in a Fischer pistol
at 115°C in a water-jet pump vacuum for 3 h. The oil obtained was dissolved in DMSO-d6 (1.5 ml) and the
1H NMR spectrum taken. The spectrum was interpreted by comparison with the spectra of compounds 3b and 5.
The dehaloalkylation product obtained was mainly a mixture of compounds 3b and 5 in a molar ratio of 3:2 (the
composition was estimated from the integrated intensities of the C-methyl group signals).
We are grateful to Aventis CropScience for financial support.
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