Structure and tautomerism of 4-substituted 3(5)-aminopyrazoles in solution and in the solid state: NMR study and Ab initio calculations

Article abstract of DOI:10.1134/S1070428014030191

Annular tautomerism of 3(5)-aminopyrazoles containing a cyano, thiocyanato, or aryl substituent in the 4-position has been studied by ¹H and ¹³C NMR in solution, cross-polarization and magic-angle spinning ¹³C NMR in the s

Full text of DOI:10.1134/S1070428014030191

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 3, pp. 412–421. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © E.E. Emelina, A.A. Petrov, D.V. Filyukov, 2014, published in Zhurnal Organicheskoi Khimii, 2014, Vol. 50, No. 3, pp. 424–433.
Structure and Tautomerism of 4-Substituted
3
(5)-Aminopyrazoles in Solution and in the Solid State:
NMR Study and Ab Initio Calculations
E. E. Emelina, A. A. Petrov, and D. V. Filyukov
St. Petersburg State University, Universitetskii pr. 26, St. Petersburg, 198504 Russia
e-mail: emelina@hotmail.ru
Received October 30, 2013
Abstract—Annular tautomerism of 3(5)-aminopyrazoles containing a cyano, thiocyanato, or aryl substituent in
1
13
the 4-position has been studied by H and C NMR in solution, cross-polarization and magic-angle spinning
1
3
C NMR in the solid state, and ab initio quantum chemical calculations (B3LYP/6-31G**). The title com-
pounds in the solid state exist as 3-amino tautomers. A rare case of slow (on the NMR time scale) annular
prototropic tautomerism has been observed in DMSO-d : signals of particular tautomers (3- and 5-aminopyra-
zoles) have been detected in the NMR spectra. 4-Cyano and 4-thiocyanato derivatives exist preferentially as
6
5
-amino tautomers, whereas 4-methoxy analog is represented mainly by the 3-amino tautomers. Ab initio
calculations (B3LYP/6-31G**) for the gas phase and DMSO solution (in terms of the polarizable continuum
model) have shown increase of the relative stability of more polar 5-amino tautomer in going to DMSO.
DOI: 10.1134/S1070428014030191
3
(5)-Aminopyrazoles are important intermediate
Annular tautomerism in the series of 3(5)-amino-
1H-pyrazoles in solution under normal conditions is
a very fast process [10–14], and spectral parameters of
particular tautomers can generally be determined only
at low temperature [10, 11]. However, 3(5)-amino-
5(3)-phenylpyrazole displayed signals from two tauto-
products in the synthesis of heterocyclic compounds
exhibiting diverse biological activity [1, 2]. The spec-
trum of biological activity of N-unsubstituted
3
(5)-aminopyrazoles also continuously extends. These
compounds have recently been shown to act as poten-
tial inhibitors of Aurora C kinase and protein kinases C
and exhibit antitumor and antimicrobial activity [3–9].
1
13
mers in the H and C NMR spectra in DMSO-d at
6
room temperature. Increase in the electron-withdraw-
ing power of the X-substituent in 3(5)-amino-5(3)-
3
(5)-Aminopyrazoles having no substituent on the
endocyclic nitrogen atom are potentially tautomeric
10–14]. Processes involving proton transfer are
(
X-phenyl)pyrazoles was shown to raise the fraction of
the 5-amino tautomer [16]. We previously identified
[
1
signals belonging to different tautomers in the H and
responsible for many chemical, physicochemical, and
biological properties of these heterocycles. Determina-
tion of the molecular and supramolecular structures of
1
3
1
C NMR spectra of 3(5)-amino-5(3)-R -4-cyanopyra-
1
zoles and 3(5)-amino-5(3)-R -4-thiocyanatopyrazoles
in DMSO-d at 20°C [17]. Elguero et al. [18, 19]
3
(5)-aminopyrazoles is important not only for detailed
6
1
13
determined the H and C chemical shifts and the ratio
of 3- and 5-aryl tautomers of 4-halo-3(5)-arylpyrazoles
studies of mechanisms of their reactions, where the
reactivity may be controlled by a particular tautomeric
form. It is also necessary from the viewpoint of molec-
ular recognition problem and structure–biological
activity correlations. Despite obvious significance and
topicality of quantitative studies on protolytic equi-
libria of nitrogen heterocycles for prediction of their
reactivity, chemical properties, biological activity, and
complexing ability, as well as for structure determina-
tion of metal coordination compounds derived there-
from [15], relevant systematic data remain insufficient.
in THF-d at –82°C and DMSO-d at 27°C. Kusakie-
8
6
wicz-Dawid et al. [20] revealed the presence of two
tautomers of ethyl 3(5)-amino-5(3)-methylpyrazole-4-
carboxylate in DMSO-d .
6
In the present work we examined by NMR spec-
troscopy how the substituent in position 4 of the
1
2
heterocycle of 3(5)-amino-5(3)-R -4-R -pyrazoles I–
IV affects their tautomer composition (Scheme 1) in
solution and in the solid state and estimated the
4
12

STRUCTURE AND TAUTOMERISM OF 4-SUBSTITUTED 3(5)-AMINOPYRAZOLES
413
Scheme 1.
structure of the tautomers was identified by comparing
1
R2
R2
the chemical shifts of the CNH and CR endocyclic
2
carbon atoms in Id, IIId, and IVd with those observed
R1
NH2
R1
NH2
13
in the CPMAS C NMR spectrum of 5-amino-1-
N
N
N
N
(cyclohexylmethyl)-3-methyl-4-phenyl-1H-pyrazole
1
3
H
H
(
V-5A), as well as with the C NMR chemical shifts
3
A
I–IV
5A
of 5- and 3-amino-substituted pyrazoles VI–XIII in
DMSO-d (Table 2). Similarity between the chemical
2
1
6
I, R = CN, R = H (a), Me (b), 4-MeC
6
H
4
H
(c), Ph (d);
(b), Ph (c),
2
1
shifts of the ring carbon atoms in pyrazoles in solution
and in the solid state was noted in [22].
II, R = SCN, R = 4-MeOC
-BrC (d), 4-ClC
a), Ph (b), 4-ClC
-MeOC (a), Ph (b), 4-ClC
6
H
4
(a), 4-MeC
6
4
1
2
4
(
6
H
4
6
H
4
(e); III, R = H, R = 4-MeOC
6
H
4
1
2
6
H
4
(c), 3-BrC
6
H
4
H
(d); IV, R = Me, R =
(c), 3-ClC (d).
The structure of 5-amino-1-benzyl-4-cyano-3-
phenyl-1H-pyrazole (VI) was determined taking into
account couplings between the ortho protons in the
4
6
H
4
6
4
6 4
H
3
3
3
stability of particular tautomers by ab initio quantum
phenyl ring on C and C (δ 149.30 ppm, J
=
C
CH
chemical calculations.
3
.6 Hz) and between protons in the 1-CH group and
2
5 3 13
C (δ 153.39 ppm, J = 2.5 Hz). The C chemical
Depending on the substituent nature, 3(5)-amino-
C
CH
shifts of 1-benzyl-4-phenyl-1H-pyrazol-5- and
5
(3)-arylpyrazoles in crystal may exist as one or two
-
3-amines VIII and IX were reported by us in [23],
tautomers [16, 21]. The cross-polarization magic-angle
1
3
while the data for aminopyrazoles XI–XIII were taken
spinning (CPMAS) C NMR spectra of crystalline
from [16, 24].
4
-substituted 3(5)-aminopyrazoles Id, IIId, and IVd
1
are given in Table 1. The spectra contain only one set
The positions of the CR and CNH signals in the
CPMAS C NMR spectra of Id, IIId, and IVd are
2
1
3
of signals which may be assigned to tautomer 3A. The
Table 1. Solid-state CPMAS 13C NMR spectra of pyrazoles Id, IIId, and IVd (tautomer 3A) and 1-(cyclohexylmethyl)-3-
methyl-4-phenyl-1H-pyrazole (V-5A)
Chemical shifts δ , ppm
C
Compound
no.
R1
R2
CR1
C4
R1, R2
CNH
159.93 113.74 (CN), 128.15 (C
152.01 119.03, 124.56, 127.84, 131.58 (C
153.07 10.99 (CH ), 126.03, 132.26, 135.04 (C
144.60 11.39 (CH ), 25.60, 26.94, 30.25, 30.19, 38.50 (C
3.97 (CH ), 125.87, 128.85, 134.53 (C
2
Id-3A
Ph
H
Me
Me
CN
3-BrC
145.77
131.58
139.16
144.60
074.59
107.32
103.16
102.78
6
5
H )
IIId-3A
IVd-3A
V-5A
6
H
4
6
H )
4
3-ClC
Ph
6
H
4
3
6
H )
4
3
6
H11),
5
2
6
H )
5
1
13
Table 2. Chemical shifts of the CR and CNH
2
carbon atoms in the C NMR spectra of pyrazoles VI–XIII in DMSO-d
6
C
δ , ppm
Compound no.
Tautomer
R1
R2
N-R
CR1
CNH
2
VI
VII
5A
5A
5A
3A
5A
5A
3A
5A
Ph
4-MeC
H
CN
SCN
Ph
Ph
Ph
H
H
H
H
CH
2
2
2
2
2
Ph
149.30
151.20
137.20
129.10
144.07
147.10
138.30
149.50
142.40
153.39
152.60
143.20
152.40
143.90
145.00
152.80
149.50
156.20
6
H
4
CH
CH
CH
CH
Bu
Bu
H
Ph
Ph
Ph
Ph
a
VIII
IXa
H
X
Me
Me
Me
Ph
XI b
XIIb
XIIIc
3
A
Ph
H
a
Data of [23]; b data of [24]; c data of [16].
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 3 2014

4
14
EMELINA et al.
N
Ia and Ib [21] and ethyl 3(5)-amino-5(3)-methylpyr-
H
azole-4-carboxylate [20] in crystal also have the struc-
ture of 3-amino tautomers 3A.
NH2
153.39 ppm
JCH = 3.6 Hz
δ
C
The ratio of tautomers of I–IV in DMSO-d at 20°C
6
3
N
N
1
13
H
was determined by H and C NMR (Table 3). The
spectra of 3(5)-amino-5(3)-aryl-4-cyanopyrazoles Ic
and Id and 3(5)-amino-5(3)-aryl-4-thiocyanatopyra-
zoles IIa and IIb contained double signals from the
CH2
δ
C
J
149.30 ppm
CH = 3.6 Hz
3
NH and NH protons, and compound Ic displayed
2
1
close to those observed for the 3-amino tautomers of
structurally related compounds IX, XII, and XIII but
are considerably different from the positions of the
corresponding signals of model 5-amino derivatives
double signals from the CR and CNH carbon atoms
2
1
3
in the C NMR spectrum (Fig. 1). We failed to iden-
tify carbon signals belonging to the minor tautomer of
Id, IIa, and IIb because of its low concentration and
signal broadening. The observed signals were assigned
by comparing with the spectra of model 3-amino- and
5-aminopyrazoles (Table 2) [17]. In all cases, tautomer
5A predominates in solution, whereas crystalline
compounds Ia, Ib, and IIb are represented by 3-amino
tautomer 3A [21].
VI, VIII, X, XI, and XIII. The difference in the δ
C
1
values of the CR and CNH carbon atoms for Id, IIIc,
2
and IVa exceeds 10 ppm, which also confirms the
3
-amino structure of these compounds: the correspond-
ing difference for 5-aminopyrazoles is at least twice as
low [12, 16, 17, 23].
Thus, compounds Id, IIId, and IVd in the solid
state exists as tautomers 3A. According to the X-ray
diffraction data, 4-cyano-substituted amino pyrazoles
As follows from the tautomer ratio of Ia–Id, IIa–
IIe, and 3(5)-amino-5(3)-arylpyrazoles [16], introduc-
tion of an electron-withdrawing substituent (such as
5
A-NH
2
2
H O
5
A-NH
3
A-NH
2
3
A-NH
δ, ppm
2
H O
4
3
A-NH
2
6
8
5
A-NH
2
1
1
0
2
5
A-NH
A-NH
3
1
2
10
8
6
4
δ, ppm
Fig. 1. NOESY spectrum of 5(3)-amino-3(5)-(4-methylphenyl)-1H-pyrazole-4-carbonitrile in DMSO-d
6
.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 3 2014

STRUCTURE AND TAUTOMERISM OF 4-SUBSTITUTED 3(5)-AMINOPYRAZOLES
415
1
CN or SCN group) into position 4 of the pyrazole ring
induces considerable shift of the equilibrium toward
tautomer 5A. The NOESY–EXSY experiment for
Table 3. Tautomeric composition of 3(5)-amino-5(3)-R -
2
4
-R -1H-pyrazoles (DMSO-d
6
, 20°C)
Compound
no.
R1
R2
5
(3)-amino-3(5)-(4-methylphenyl)-1H-pyrazole-4-
5A, % 3A, %
carbonitrile (IIId) showed that proton transfer between
Iaa
Ib
Ic
Id
IIa
H
Me
4-MeC
Ph
4-MeOC
4-MeC
Ph
4-BrC
4-ClC
H
CN
CN
CN
CN
SCN
SCN
SCN
SCN
SCN
4-MeOC
1000
63
75
72
70
76
81
82
87
30
–
the endocyclic nitrogen atoms in DMSO-d is mediat-
6
a
ed by water molecules.
37
25
28
30
24
19
18
13
70
6
H
4
4
-Aryl-substituted aminopyrazoles IIIb, IIIc, and
1 13
IVa–IVc in DMSO-d displayed in the H and
C
6
NMR spectra only one set of signals, and the NH
6
H
2
4
(
δ ~4.5 ppm) and NH signals (δ ~11.5 ppm) in the
IIb
6
H
4
1
1
H NMR spectra and CR and CNH signals in the
IIca
2
1
3
C NMR spectra were broadened. The spectral pattern
a
IId
6
H
4
did not change in going to DMF-d at –20 or –40°C.
7
IIea
H
6
4
The observed signal broadening indicates the existence
of tautomeric equilibrium with fairly high rate of the
IIIa
6
H
4
mutual transformation 3A
5A, so that the average
a
Data of [17].
1
signals of both tautomers are observed in the H and
1
3
C NMR spectra. We succeeded in detecting signals of
the pyrazole ring plane and HNH plane of the amino
1
13
particular tautomers only in the H and C NMR spec-
1
group does not exceed 4°. The N H hydrogen atom
tra of 4-(4-methoxyphenyl)-1H-pyrazol-3(5)-amine
does not deviate from the pyrazole ring plane. The
(
3
IIIa) in DMSO-d , where the fraction of tautomer
4
6
dihedral angle between the phenyl ring on C and the
A was 70%.
pyrazole ring in aminopyrazole IIIb in the gas phase is
larger by ~9° for tautomer 3A than for 5A, and it
insignificantly decreases for both tautomers in going to
DMSO solution (~2°).
The ratios of tautomers 3A and 5A in solutions of
-aryl-substituted aminopyrazoles IIIb–IIId and IVa–
4
IVd were estimated according to the additivity scheme
with the use of model compounds [17, 21, 23] and
increments of substituents in the pyrazole ring taken
from [12]. All the examined 4-aryl-substituted amino-
pyrazoles in DMSO exist mainly as tautomer 3A (~60–
The calculated geometric parameters of pyrazoles
Ia and Ib are consistent with the X-ray diffraction data
[
21]. The bond lengths and bond angles in the pyrazole
ring of each tautomer (3A and 5A) change insignifi-
cantly on variation of the 4-substituent: the difference
in the bond lengths does not exceed 0.5–0.7%
7
0%). This very approximate estimate is quite consis-
tent with the experimental data for compound IIIa.
Thus, the most favorable tautomer of 4-aryl-substi-
tuted 3(5)-aminopyrazoles in DMSO solution is 3A,
whereas aminopyrazoles having an electron-withdraw-
(
3
Table 5). The maximum electron density in tautomers
A and 5A is localized on the amino nitrogen atom.
The negative charge in the pyrazole ring is localized
mainly on the nitrogen atoms; in going from the gas
phase to DMSO solution, the charge on N(H) remains
4
ing substituent on C (CN or SCN group) exist mainly
as tautomer 5A.
2
With a view to estimate energy parameters of par-
ticular tautomers and compare them with the experi-
mental compositions of tautomeric mixtures, the mo-
lecular structure of 4-substituted aminopyrazoles I–IV
was simulated by quantum chemical methods. The
calculations were performed ab initio at the B3LYP/
almost unchanged, whereas the charge on N increases
in both tautomers. The orders of bonds in the pyrazole
ring indicate essential π-electron density delocalization
both in the gas phase and in solution.
The calculated (B3LYP/6-31G**) total energies of
tautomers 3A and 5A of Ia, Ib, and IIIb in the gas
phase and DMSO solution are given in Table 4. Tau-
tomers 3A turned out to be more stable than 5A in the
gas phase; the energy difference between the tautomers
of 4-cyano derivatives is ~1 kcal/mol, and it attains
2 kcal/mol for 4-phenyl-substituted aminopyrazole
IIIb. These data are in a good agreement with the exis-
tence of compounds Ia, Ib, and IIIc in crystal as tauto-
6
-31G** level of theory with the use of the polarizable
continuum model (PCM) to include solvent effects
(
see Experimental). The calculation results for
tautomers 3A and 5A of pyrazoles Ia, Ib, and IIIb are
presented in Tables 4 and 5.
~
In all calculated structures atoms in the pyrazole
ring lie in one plane, and the dihedral angle between
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 3 2014

4
16
EMELINA et al.
Table 4. Calculated (B3LYP/6-31G**) total energies, zero-point vibration energies, Gibbs energies, enthalpies, differences in
the Gibbs energies and enthalpies, and dipole moments of tautomers 3A and 5A of aminopyrazoles Ia, Ib, and IIIb in the gas
phase and DMSO solutiona
G°298
,
H°298
,
ΔEtot
,
ΔG°298
,
ΔH°298,
Compound no.
Ia (gas phase)
E
tot, hartree
ZPE
μ, D Δμ, D
kcal/mol kcal/mol kcal/mol kcal/mol kcal/mol
3A –373.60446 054.553
35.137
35.114
35.324
34.453
50.120
51.203
51.632
51.433
84.269
84.057
84.590
84.467
059.434
059.509
059.484
059.064
77.95
077.899
078.171
078.036
112.944
112.893
113.143
113.058
–1.1734
–0.0000
–0.3326
–0.0000
0.023
0.000
0.871
0.000
–0.075
0.000
0.420
0.000
4.224 0.943
5.167
5.558 1.635
7.193
4.307 0.494
4.801
5.617 0.903
6.720
1.673 1.598
3.271
2.331 2.141
4.472
5
A
–373.60259 054.595
3A –373.62199 054.682
–373.62146 054.045
3A –412.90091 071.849
–412.89891 071.929
3A –412.91827 072.342
–412.91764 072.125
IIIb (gas phase) 3A –512.32144 106.333
–512.31777 106.226
3A –512.33445 106.612
–512.33228 106.496
Ia (DMSO)
Ib (gas phase)
Ib (DMSO)
5
A
–1.2550 –1.083– 0.051
5
A
–0.0000
–0.3953
–0.0000
–2.3030
–0.0000
–1.3617
–0.0000
0.000
0.199
0.000
0.212
0.000
0.123
0.000
0.000
0.135
0.000
0.051
0.000
0.085
0.000
5
A
5
A
IIIb (DMSO)
5
A
a
The data for DMSO solution were obtained using the polarizable continuum model (PCM).
mers 3A, which was determined experimentally (see
suggests that the tautomeric equilibrium could readily
be displaced in any direction by intermolecular inter-
actions in solution. The state of tautomeric equilibrium
can be roughly estimated on the basis of dipole
moments (Table 4, Fig. 2). Both in the gas phase and in
above). In DMSO solution the difference in the stabil-
ities of tautomers 3A and 5A is smaller, and the ΔE
tot
value for aminopyrazoles Ia and Ib becomes negli-
gible. The small energy difference between tautomers
I-3A
I-5A
II-3A
II-5A
IIIb-3A
IIIb-5A
Fig. 2. Calculated (B3LYP/6-31G**) dipole moment vectors of tautomers 3A and 5A of aminopyrazoles Ia, Ib, and IIIb.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 3 2014

STRUCTURE AND TAUTOMERISM OF 4-SUBSTITUTED 3(5)-AMINOPYRAZOLES
417
Table 5. Bond lengths, bond orders, and charges on atoms in the pyrazole ring in tautomers 3A and 5A of aminopyrazoles Ia,
Ib, and IIIb, calculated at the B3LYP/6-31G** level of theory for the gas phase and DMSO solution (using the polarizable
continuum model)
Ia
Ib
IIIb
Parameter
gas phase
5A
Bond lengths in the pyrazole ring and amino group (d, Å)
DMSO
gas phase
DMSO
gas phase
3A 5A
DMSO
3A 5A
3
A
3A 5A
3A 5A
3A 5A
N–Ha
N–N
1.007 1.008 1.010 1.010 1.008 1.008 1.011 1.010 1.007 1.008 1.008 1.010
1.366 1.372 1.368 1.376 1.369 1.374 1.371 1.378 1.361 1.367 1.363 1.369
1.343 1.319 1.337 1.319 1.346 1.322 1.341 1.321 1.351 1.325 1.347 1.328
1.392 1.427 1.396 1.427 1.398 1.435 1.403 1.435 1.389 1.424 1.392 1.422
1.435 1.401 1.436 1.409 1.434 1.399 1.435 1.408 1.433 1.397 1.433 1.403
1.330 1.353 1.331 1.351 1.328 1.352 1.330 1.350 1.331 1.358 1.334 1.357
1.379 1.379 1.381 1.364 1.380 1.379 1.381 1.367 1.397 1.395 1.398 1.387
1.011 1.013 1.013 1.011 1.011 1.012 1.013 1.012 1.014 1.015 1.015 1.015
1.011 1.012 1.013 1.012 1.011 1.013 1.012 1.012 1.014 1.014 1.015 1.014
1.080 1.081 1.080 1.082 1.493 1.495 1.492 1.495 1.081 1.083 1.080 1.083
1.414 1.413 1.411 1.408 1.413 1.412 1.409 1.407 1.469 1.467 1.470 1.468
1
N–C(R )
1
2
C(R )–C(R )
2
C(R ) –C(NH
2
)
N–C(NH )
2
C–NH
2
b
N–H
b
N –H
1
C–R
C–R2
Orders of bonds in the pyrazole ring and amino group
N–Ha
N–N
0.891 0.894 0.870 0.875 0.895 0.896 0.876 0.877 0.897 0.898 0.879 0.881
1.141 1.133 1.139 1.126 1.129 1.117 1.127 1.112 1.149 1.146 1.147 1.144
1.153 1.507 1.194 1.510 1.084 1.466 1.121 1.470 1.106 1.479 1.135 1.463
1.427 1.280 1.393 1.280 1.403 1.264 1.367 1.263 1.462 1.305 1.441 1.320
1.278 1.379 1.275 1.336 1.259 1.367 1.255 1.323 1.301 1.415 1.307 1.390
1.390 1.063 1.389 1.079 1.394 1.060 1.392 1.075 1.397 1.040 1.387 1.057
1.030 1.025 1.041 1.067 1.025 1.018 1.037 1.059 0.990 0.993 1.000 1.017
0.892 0.887 0.884 0.879 0.893 0.888 0.885 0.879 0.894 0.885 0.885 0.878
0.894 0.895 0.884 0.878 0.894 0.895 0.884 0.879 0.896 0.899 0.888 0.884
0.936 0.949 0.928 0.945 1.025 1.027 1.031 1.027 0.936 0.949 0.931 0.946
0.962 0.967 0.978 0.991 0.966 0.965 0.984 0.990 1.032 1.023 1.035 1.033
1
N–C(R )
1
2
C(R )–C(R )
2
C(R )–C(NH
2
)
N–C(NH )
2
C–NH
N–Hb
2
b
N–H
C–R1
C–R2
Mulliken charges on atoms in the pyrazole ring and amino group
(
N)Ha
+0.289 +0.282 +0.326 +0.317 +0.279 +0.278 +0.315 +0.314 +0.275 +0.270 +0.310 +0.303
–0.329 –0.401 –0.322 –0.404 –0.395 –0.407 –0.389 –0.409 –0.341 –0.402 –0.340 –0.404
–0.381 –0.292 –0.413 –0.336 –0.385 –0.352 –0.421 –0.395 –0.386 –0.310 –0.429 –0.364
+0.151 +0.129 +0.161 +0.118 +0.380 +0.326 +0.392 +0.327 +0.105 +0.086 +0.098 +0.060
+0.022 +0.010 –0.001 –0.010 –0.010 –0.001 –0.027 –0.021 –0.047 –0.067 –0.059 –0.073
+0.504 +0.547 +0.497 +0.580 +0.508 +0.554 +0.502 +0.583 +0.435 +0.479 +0.420 +0.489
–0.659 –0.663 –0.678 –0.675 –0.659 –0.664 –0.679 –0.675 –0.662 –0.663 –0.683 –0.681
+0.276 +0.292 +0.294 +0.310 +0.274 +0.291 +0.292 +0.309 +0.259 +0.270 +0.279 +0.290
+0.274 +0.273 +0.293 +0.310 +0.273 +0.272 +0.292 +0.309 +0.264 +0.260 +0.280 +0.294
a
N(H)
N
C(R )
C(R )
C(NH )
NH
H
H
1
2
2
2
c
c
a
b
c
Nitrogen atom in the pyrazole ring.
Nitrogen atom in the amino group.
Hydrogen atom in the amino group.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 3 2014

4
18
EMELINA et al.
DMSO solution the dipole moments of tautomeric
potential energy surfaces were identified by calculating
vibrational frequencies.
4
-cyano-substituted aminopyrazoles Ia and Ib are
larger than those for 4-phenyl analog IIIb, and the
dipole moments of tautomers 3A are always smaller
than the dipole moments of 5A. The dipole moment of
all structures increases in going from the gas phase to
polar DMSO, but the observed increase for tautomer
Compounds Ic and Id were synthesized from the
corresponding (alkoxyarylmethylidene)malononitriles
and hydrazine hydrate according to the procedure
described in [27].
3
(5)-Amino-5(3)-(4-methylphenyl)-1H-pyrazole-
-carbonitrile (Ic). Yield 73%, mp 176–178°C (from
MeOH–H O); published data [28]: mp 173–178°C
3
A is considerably smaller than for more polar (and
4
hence solvated more efficiently) tautomer 5A. Presum-
ably, tautomer 5A of Ia and Ib should predominate in
such polar solvent as DMSO. 4-Phenyl-substituted
aminopyrazole IIIb is characterized by a smaller
dipole moment and larger difference in the stability of
tautomers 3A and 5A; therefore, a larger fraction of
tautomer 3A in the equilibrium mixture in solution
may be expected. In fact, the fraction of tautomer 5A
in DMSO for compounds with electron-withdrawing
substituents (4-CN, 4-SCN) is 80–100%, whereas
2
(
EtOH–H O).
2
1
Tautomer 3A. H NMR spectrum, δ, ppm: 5.57 br.s
(
2H, NH ), 7.26–7.71 m (4H, C H ), 12.76 br.s (1H,
2
6
4
1
13
N H). C NMR spectrum, δ , ppm: 21.71 (CH ),
C
3
5
1
(
17.13 (CN), 143.66 br.s (C ); 128.36, 131.00, 138.96
3 4
C
); 159.66 br (C ); the C signals was not iden-
arom
tified because of broadening.
1
Tautomer 5A. H NMR spectrum, δ, ppm: 6.48 br.s
(
2H, NH ), 7.26–7.71 m (4H, C H ), 12.09 br.s (1H,
4
-aryl-substitued analogs are represented by 60–70%
2
6
4
1 13
N H). C NMR spectrum, δ , ppm: 21.71 (CH ),
of tautomer 3A.
C
3
4
7
0.28 br (C ), 117.13 (CN); 126.45, 130.17, 138.90
3 5
(
C
); 150.90 br (C ), 155.30 br (C ).
EXPERIMENTAL
arom
3
(5)-Amino-5(3)-phenyl-1H-pyrazole-4-carboni-
The H and 13C NMR spectra were recorded on
1
trile (Id). Yield 85%, mp 202°C [29].
a Bruker DPX-300 spectrometer at 300.13 and
1
Tautomer 3A. H NMR spectrum, δ, ppm: 5.60 br.s
7
5.47 MHz, respectively (DMSO-d , 22°C); the chem-
6
(
2H, NH ), 7.32–7.85 m (5H, Ph), 12.84 br.s (1H,
2
ical shifts were measured relative to the residual proton
and carbon signals of the deuterated solvent
1 13
N H). The C NMR spectrum was not recorded be-
cause of the low concentration and signal broadening.
(
DMSO-d , δ 2.50 ppm; δ 39.50 ppm). The solid-
5
C
1
13
Tautomer 5A. H NMR spectrum, δ, ppm: 6.44 br.s
phase CPMAS C NMR spectra were obtained at
0°C on a Bruker Avance II-500 instrument (125 MHz;
(
2H, NH ), 7.32–7.85 m (5H, Ph), 12.15 br.s (1H,
2
2
1
1
3
4
N H). C NMR spectrum, δ , ppm: 71.34 br (C ),
C
contact time 4 ms; rotation speed 10 kHz); samples
were placed into zirconium oxide rotors with a diam-
eter of 4 mm. The high-resolution mass spectra were
recorded on a Bruker Daltonics microTOF spectrom-
eter (positive electrospray ionization). The elemental
compositions were determined on a Hewlett Packard
HP-185B CHN analyzer.
3
5
1
1
17.06 (CN), 150.09 br (C ), 156.30 br (C ); 132.07,
29.65, 126.54 (Ph).
Compounds IIa and IIb were synthesized accord-
ing to the procedure described in [30].
5
(3)-(4-Methoxyphenyl)-4-thiocynato-1H-pyra-
zol-3(5)-amine (IIa). Yield 73%, mp 146°C, mixture
1
of tautomers. H NMR spectrum (DMSO-d + one
6
Ab initio calculations were carried out using
GAMESS-US software package [25]. Initially, geo-
metric parameters were optimized by the Hartree–Fock
method with 6-31G basis set, the data obtained were
used as starting ones for the optimization at the DFT
B3LYP/6-31G** level, and thermodynamic parameters
were calculated for the optimized structures. The same
structures were used as input data in the DFT
B3LYP/6-31G** calculations with inclusion of solvent
effects in terms of the PCM model [26], and thermo-
dynamic parameters were calculated from the results.
In all cases, geometric parameters were optimized
without symmetry restrictions, and local minima on the
drop of CF COOH), δ, ppm: 5.84 br.s (2H, NH );
3
2
7
.05 m, 7.08 m, 7.69 m, 7.72 m (4H, C H ); 12.17 br.s
6
4
1
13
(
1H, N H). C NMR spectrum, δ , ppm: 56.07
C
4
(
OCH ), 74.57 br (C ), 114.95 (SCN); 124.18, 129.42,
3
3
(5)
1
60.38 (C ); 149.48 br (C ), 155.66 br (CNH ).
arom
2
1
Tautomer 3A. H NMR spectrum, δ, ppm: 5.47 br.s
2H, NH ), 7.05–7.72 m (4H, C H ), 12.39 br.s
(
(
2
6
4
1
1H, N H).
Tautomer 5A. H NMR spectrum, δ, ppm: 5.99 br.s
(2H, NH ), 7.05–7.72 m (4H, C H ), 12.11 br.s (1H,
1
2
6
4
1
N H). Found, %: C 53.25; H 4.17. C H N OS. Calcu-
lated, %: C 53.64; H 4.09.
11
10
4
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 3 2014

STRUCTURE AND TAUTOMERISM OF 4-SUBSTITUTED 3(5)-AMINOPYRAZOLES
419
5
(3)-(4-Methylphenyl)-4-thiocyanato-1H-pyra-
ppm: 4.85 s (2H, NH ), 7.34–7.55 m (4H, C H ), 7.71
2
6
4
1
3
zol-3(5)-amine (IIb). Yield 65%, mp 121°C.
(1H, CH), 11.78 s (1H, NH). C NMR spectrum, δ ,
C
4
1
ppm: 105.32 (C ), 131.81 (CH), 150.25 (CNH );
2
Tautomer 3A. H NMR spectrum, δ, ppm: 2.35 s
1
33.88, 129.57, 129.55, 127.86 (C H ). Found: m/z
6
4
(
7
3H, CH ), 5.45 br.s (2H, NH ); 7.29 m, 7.31 m,
3
2
+
+
1
194.0493 [M + H] . C H ClN . Calculated: [M + H]
9
9
3
.64 m, 7.67 m (4H, C H ); 12.58 br.s (1H, N H).
6
4
1
94.0480.
1
Tautomer 5A. H NMR spectrum, δ, ppm: 2.35 s
3H, CH ), 6.06 br.s (2H, NH ); 7.29 m, 7.31 m,
4
-(3-Bromophenyl)-1H-pyrazol-3(5)-amine
(
3
2
1
(IIId). Yield 71%, mp 130–132°C (from MeCN).
7
.64 m, 7.67 m (4H, C H ); 12.12 br.s (1H, N H).
6
4
1
1
3
H NMR spectrum, δ, ppm: 4.89 s (2H, NH ), 7.26–
2
C NMR spectrum, δ , ppm: 21.74 (CH ), 72.90 br
C
3
4
7.76 m (4H, C H ), 7.71 s (1H, CH), 11.79 s (1H, NH).
6
4
(
1
C ), 114.63 s (SCN); 127.99, 130.03, 138.86 (C );
arom
1
3
4
3
5
C NMR spectrum, δ , ppm: 105.15 (C ), 131.82
C
48.50 br (C ), 155.41 br (C ). Found, %: C 57.07;
(
CH), 150.15 (CNH ); 123.01, 124.97, 127.85, 128.42,
2
H 4.58. C H N S. Calculated, %: C 57.37; H 4.38.
11
10
4
+
1
31.40, 137.54 (C H ). Found: m/z 237.9988 [M + H] .
6
4
3
(5)-Amino-5(3)-alkyl-4-aryl-1H-pyrazoles IIIa–
+
C H BrN . Calculated: [M + H] 237.9974.
9
9
3
IIId and IVa–IVd (general procedure). Hydrazine
4
-(4-Methoxyphenyl)-3(5)-methyl-1H-pyrazol-
hydrate, 50 mmol, was added dropwise to a solution of
5
(3)-amine (IVa). Yield 71%, mp 139–140°C (from
2
5 mmol of the corresponding ketonitrile in 50 mL of
1
EtOAc). H NMR spectrum, δ, ppm: 2.14 s (3H, Me),
.76 s (3H, CH O), 4.42 s (2H, NH ), 6.93–7.27 m
ethanol and 5 mL of acetic acid. The mixture was
stirred for 2 h at 50°C, an additional 10 mL of acetic
acid was added, and the mixture was heated for 5 h
under reflux, cooled to room temperature, poured into
3
(
3
2
1
3
4H, C H ), 11.09 s (1H, NH). C NMR spectrum, δ ,
6
4
C
4
ppm: 11.92 (CH ), 55.86 (CH O), 104.79 (C ), 137.90
3
3
(
1
CMe), 151.70 (CNH ); 114.86, 127.17, 129.93,
2
2
00 mL of ice water, and neutralized to pH 9 by adding
aqueous ammonia. The precipitate was filtered off,
dried in air, and purified by recrystallization.
+
57.76 (C H ). Found: m/z 204.1144 [M + H] .
6
4
+
C H N O. Calculated: [M + H] 204.1131.
1
1
14
3
3
(5)-Methyl-4-phenyl-1H-pyrazol-5(3)-amine
4
-(4-Methoxyphenyl)-1H-pyrazol-3(5)-amine
(
IVb). Yield 73%, mp 138–139°C (from MeCN);
(
IIIa). Yield 70%, mp 202–203°C (from MeCN),
1
published data [33]: mp 138–140°C. H NMR spec-
trum, δ, ppm: 2.17 s (3H, Me), 4.45 s (2H, NH ), 7.17–
.39 m (4H, C H ), 11.29 s (1H, NH). C NMR spec-
a mixture of tautomers; published data [31]: mp 198–
1
2
2
4
5
01°C. H NMR spectrum, δ, ppm: 3.74 s (3H, CH O),
3
13
7
6
4
.52 br.s (1.4H, NH in 3A), 4.98 br.s (0.6H, NH in
2
2
4
trum, δ , ppm: 11.41 (CH ), 104.12 (C ), 138.00
C
3
A), 6.89–7.43 (4H, C H ), 7.61 br.s (1H, CH),
6
4
(
1
CMe), 150.90 (CNH ); 125.03, 127.92, 128.62,
2
1
1.65 br.s (1H, NH).
+
34.33 (Ph). Found: m/z 174.1041 [M + H] . C H N .
1
0
12
3
1
3
Tautomer 3A. C NMR spectrum, δ , ppm: 106.85
+
C
Calculated: [M + H] 174.1026.
-(4-Chlorophenyl)-3(5)-methyl-1H-pyrazol-
4
(
1
C ), 126.84 (CH), 151.42 (CNH ), 55.01 (CH O);
2
3
4
14.02, 126.48, 158.62 (C H ).
1
6
4
5
(3)-amine (IVc) [34]. H NMR spectrum, δ, ppm:
1
3
Tautomer 5A. C NMR spectrum, δ , ppm: 55.01
C
2.17 s (3H, Me), 4.62 s (2H, NH ), 7.34–7.41 m (4H,
2
4
3
5
13
(
CH O), 102.52 (C ), 137.66 (C ), 143.69 (C NH );
3
2
C H ), 11.40 s (1H, NH). C NMR spectrum, δ , ppm:
6
4
C
4
1
14.02, 126.48, 158.62 (C H ). Found: m/z 190.0998
6
4
12.16 (CH ), 103.85 (C ), 138.75 (CMe), 151.82
3
+
+
[
M + H] . C H N O. Calculated: [M + H] 190.0975.
1
0
12
3
(CNH ); 129.24, 130.12, 130.27, 133.98 (C H ).
2
6
4
4
-Phenyl-1H-pyrazol-3(5)-amine (IIIb). Yield
4
-(3-Chlorophenyl)-3(5)-methyl-1H-pyrazol-
7
5%, mp 173–174°C (from MeCN); published data
5(3)-amine (IVd) [35]. Yield 71%, mp 128–131°C.
1
1
[
32]: mp 174–176°C. H NMR spectrum, δ, ppm:
.76 s (2H, NH ); 7.11 t (1H), 7.32 t (2H), and 7.49 d
H NMR spectrum (DMSO-d –CCl ), δ, ppm: 2.18 s
6
4
4
(3H, Me), 4.59 br.s (2H, CH ), 7.20–7.41 m (4H,
2
2
13
(
2H) (Ph); 7.67 s (1H, CH), 11.69 s (1H, NH).
C H ), 11.50 br.s (NH). C NMR spectrum
6
4
1
3
4
4
C NMR spectrum, δ , ppm: 105.62 (C ), 130.67
(DMSO-d ), δ , ppm: 11.39 (Me), 102.88 (C ), 138.20
C
6
C
(
(
CH), 149.32 (CNH ); 124.54, 125.47, 130.67, 134.07
(CMe), 150.98 (CNH ); 124.60, 126.24, 127.11,
2
2
+
Ph). Found: m/z 160.0882 [M + H] . C H N . Calcu-
130.19, 133.22, 136.54 (C H ). Found: m/z 208.0649
9
10
3
6
4
+
+
+
lated: [M + H] 160.0869.
[M + H] . C H ClN . Calculated: [M + H] 208.0637.
1
0
10
3
4
-(4-Chlorophenyl)-1H-pyrazol-3(5)-amine
1-(Cyclohexylmethyl)-3-methyl-4-phenyl-1H-
1
(
IIIc). Yield 80%, mp 146–147°C (from MeCN); pub-
pyrazol-5-amine (V). Yield 87%, mp 129°C. H NMR
1
lished data [32]: mp 141–143°C. H NMR spectrum, δ,
spectrum, δ, ppm: 0.83–1.89 m (11H, C H ), 2.08 s
6
11
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 3 2014

4
20
EMELINA et al.
(
3H, Me), 3.69 d (2H, CH , J = 7.3 Hz), 5.00 (NH ),
7. Magedov, I.V., Frolova, L., Manpadi, M., Bhoga, U.d.,
Tang, H., Evdokimov, N.M., George, O., Kathy, H.G.,
Renner, S., Getlic, M., Kinnibrugh, T.L., Fernan-
des, M.A., van Slambrouck, S., Steelant, W.F.A.,
Shuster, C.B., Rogelj, S., van Otterlo, W.A.L., and
Kornienko, A., J. Med. Chem., 2011, vol. 54, p. 4234.
8. Pevarello, P., Brasca, M.G., Orsini, P., Traquandi, G.,
Longo, A., Nesi, M., Orzi, F., Piutti, C., Sansonna, P.,
Varasi, M., Cameron, A., Vulpetti, A., Roletto, F.,
Alzani, R., Ciomei, M., Albanese, C., Pastori, W.,
Marsiglio, A., Pesenti, E., Fiorentini, F., Bischoff, J.R.,
and Mercurio, C., J. Med. Chem., 2005, vol. 48, p. 2944.
2
2
13
7
1
.10–7.40 m (5H, Ph). C NMR spectrum, δ , ppm:
C
3.47 (Me); 25.35, 26.09, 30.03, 37.72 (C H ); 52.04
6
11
4
3
2
(
CH ), 101.33 (C ), 143.02 q (C , J = 6.5 Hz),
43.62 br (C ); 124.52, 127.81, 128.47, 134.57 (Ph).
2
5
1
+
Found: m/z 270.1980 [M + H] . C H N . Calculated:
1
7
23
3
+
[
M + H] 270.1966.
5
-Amino-1-benzyl-3-phenyl-1H-pyrazole-4-car-
bonitrile (VI) [36]. Yield 85%, mp 170–172°C.
1
H NMR spectrum, δ, ppm: 5.25 (2H, CH ), 6.90 (2H,
2
NH ), 7.24 (2H), 7.29 (1H), 7.34 (2H), 7.39 (1H), 7.44
2
1
3
9
. Loehn, M., Mendez-Perez, M., Pfeiffer-Marek, S.,
Kannt, A., Begis, G., Jeannot, F., and Duclos, O., WO
Patent Appl. no. 037390, 2013; Chem. Abstr., 2013,
vol. 158, no. 418858.
(
(
2H), 7.81 (2H). C NMR spectrum, δ , ppm: 50.15 t.t
C
4 3
CH , J = 139.5, 3.6 Hz), 70.01 t (C , J = 3.3 Hz),
2
1
15.98 (CN), 131.55 t (J = 7.6 Hz); 128.74, 127.48,
1
25.70, 127.28, 128.54, 136.57 (C ); 149.30 t
arom
3
3
5
3
10. Elguero, J., Comprehensive Heterocyclic Chemistry II,
Katritzky, A.R., Rees, C.W., and Scriven, E.F.V., Eds.,
Oxford: Pergamon, 1996, vol. 4, p. 29.
(
C , J = 3.6 Hz), 153.39 t (C , J = 2.5 Hz). Found, %:
C 74.23; H 5.35. C H N . Calculated, %: C 74.43;
1
7
14
4
H 5.14.
1
1. Minkin, V.I., Garnovskii, A.D., Elguero, J., Katritz-
1
-Benzyl-3-(4-methylphenyl)-4-thiocyanato-1H-
ky, A.R., and Denisko, O.V., Advances in Heterocyclic
Chemistry, Katritzky, A.R., Ed., San Diego: Academic,
2000, vol. 76, p. 157.
pyrazol-5-amine (VII). Yield 55%, mp 115°C.
1
H NMR spectrum, δ, ppm: 2.34 s (3H, CH ), 5.25 br.s
3
(
2H, NH ), 6.54 s (2H, CH ), 7.25–7.70 m (9H, H ).
12. Begtrup, M., Boyer, G., Cabildo, P., Cativiela, C.,
Claramunt, R.M., Elguero, J., García, J.I., Toiron, C.,
and Vedsø, P., Magn. Reson. Chem., 1993, vol. 31,
p. 107.
3. Elguero, J., Comprehensive Heterocyclic Chemistry II,
Katritzky, A.R., Rees, C.W., and Scriven, E.F.V., Eds.,
Oxford: Pergamon, 1996, vol. 4, p. 1.
4. Behr, L.C., Fusco, R., and Jarboe, C.H., The Chemistry
of Heterocyclic Compounds, Weissberger, A., Ed., New
York: Interscience, 1967, p. 1.
5. Halcrow, M.A., Dalton Trans., 2009, p. 2059; Jaćimo-
vić, Ž.K., Bogdanović, G.A., Holló, B., Leovac, V.M.,
and Szécsényi, K.M., J. Serb. Chem. Soc., 2009, vol. 74,
p. 1259.
2
2
arom
1
3
C NMR spectrum, δ , ppm: 21.73 (Me), 51.53 (CH ),
C
2
4
3
7
(
2.72 br (C ), 113.70 (SCN), 151.20 br (C ), 152.60 br
C ); 128.02, 128.29, 129.33, 129.90, 130.19, 137.76,
38.39 (C ). Found, %: C 67.61; H 5.20. C H N S.
5
1
1
1
1
arom
18 16
4
Calculated, %: C 67.47; H 5.03.
The authors thank Yu.E. Moskalenko (Institute of
Macromolecular Compounds, Russian Academy of
Sciences, St. Petersburg) for recording the solid-state
NMR spectra.
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