Tautomerism of aza heterocycles: V. Structure of the spontaneous transformation products of 5-methyl-2-phenyl-3,3a,4,5,6,7-hexahydro-2H-pyrazolo- [4,3-c]pyridin-3-one in crystal and solution

Article abstract of DOI:10.1134/S1070363214060188

5-Methyl-2-phenyl-3,3a,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c]pyridin-3-one exists as zwitterion with a proton localized on the nitrogen atom of the piperidine ring and negative charge delocalized over the pyrazololate fragment. The compound is stable in crystal but ustable in solution. Its chromatographic purification and attempts to recrystallize or synthesize by condensation of phenylhydrazine with alkyl 1-methyl-4-oxopiperidin-3-carboxylate on heating in alcohols or benzene lead to the formation of a complex mixture of products. Among these products, we isolated and identified 3a,3a′-methylenebis(5- methyl-2-phenyl-3,3a,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c]pyridin-3-one), 1-methyl-3-(2-phenylhydrazinylidene)pyrrolidin-2-one, and 5-methyl-2-phenyl-3,5, 6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine. The structure of methyl 3-(2-phenylhydrazinylidene)-4,5-dihydro-3H-pyrrole-2-carboxylate and 3a,5-dimethyl-2-phenyl-3,3a,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c]pyridin-3-one was proved by NMR spectroscopy. 3a,5-Dimethyl-2-phenyl-3,3a,4,5,6,7-hexahydro- 2H-pyrazolo[4,3-c]pyridin-3-one was isolated as hydrochloride hydrate whose structure was determined by X-ray analysis.

Full text of DOI:10.1134/S1070363214060188

ISSN 1070-3632, Russian Journal of General Chemistry, 2014, Vol. 84, No. 6, pp. 1157–1178. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © A.T. Gubaidullin, V.N. Nabiullin, S.V. Kharlamov, B.I. Buzykin, 2014, published in Zhurnal Obshchei Khimii, 2014, Vol. 84, No. 6,
pp. 977–999.
Tautomerism of Aza Heterocycles:
V.1 Structure of the Spontaneous Transformation Products
of 5-Methyl-2-phenyl-3,3a,4,5,6,7-hexahydro-2H-pyrazolo-
[4,3-c]pyridin-3-one in Crystal and Solution
A. T. Gubaidullin, V. N. Nabiullin, S. V. Kharlamov, and B. I. Buzykin
Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences,
ul. Arbuzova 8, Kazan, 420088 Tatarstan, Russia
e-mail: buz@iopc.ru
Received June 17, 2013
Abstract—5-Methyl-2-phenyl-3,3a,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c]pyridin-3-one exists as zwitterion
with a proton localized on the nitrogen atom of the piperidine ring and negative charge delocalized over the
pyrazololate fragment. The compound is stable in crystal but ustable in solution. Its chromatographic
purification and attempts to recrystallize or synthesize by condensation of phenylhydrazine with alkyl 1-
methyl-4-oxopiperidin-3-carboxylate on heating in alcohols or benzene lead to the formation of a complex
mixture of products. Among these products, we isolated and identified 3a,3a′-methylenebis(5-methyl-2-phenyl-
3,3a,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c]pyridin-3-one), 1-methyl-3-(2-phenylhydrazinylidene)pyrrolidin-2-
one, and 5-methyl-2-phenyl-3,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine. The structure of methyl 3-(2-
phenylhydrazinylidene)-4,5-dihydro-3H-pyrrole-2-carboxylate
and
3a,5-dimethyl-2-phenyl-3,3a,4,5,6,7-
hexahydro-2H-pyrazolo[4,3-c]pyridin-3-one was proved by NMR spectroscopy. 3a,5-Dimethyl-2-phenyl-
3,3a,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c]pyridin-3-one was isolated as hydrochloride hydrate whose structure
was determined by X-ray analysis.
Keywords: aza cycles, dihydropyrazolone, pyrrolidin-2-one, dihydropyrrole, autoalkylation, X-ray analysis
DOI: 10.1134/S1070363214060188
In the preceding communication [1] we showed that
condensation products of phenylhydrazine with alkyl
1-alkyl-4-oxopiperidin-3-carboxylates Ia–Ic (R = Me,
Et) are not conventional CH (IIa), NH, or OH
tautomers of pyrazolone fused at the C3–C4 bond to
piperidine ring. We found that 5-methyl-2-phenyl-
3,3a,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c]pyridin-3-
one (IIa) in crystal exists as zwitterion IV with
protonated nitrogen atom of the piperidine ring and
delocalization of the negative charge over the
pyrazololate fragment; structure IV is more favorable
than that with negative charge localization on the
oxygen (structure III) or N1 nitrogen atom of the
pyrazole ring [1] (Scheme 1).
or equilibrium between zwitterionic forms III and IV
and CH, OH, and N1H tautomers is possible. The
reason is that compound IIa is almost insoluble in
nonpolar solvents and is unstable in polar solvents
(H2O, AcOH, CF3COOH, DMSO) and even in those
solvents where it is poorly soluble (alcohols, benzene,
etc.). Crystalline pyrazolopiperidine (IIa) can be stored
for many years without appreciable change (according
to the IR data). Dissolution of IIa in alcohols and
benzene and subsequent storage of these solutions
leads to formation of the same complex mixtures of
products as those obtained on attempted synthesis of
IIa in boiling solvents. The transformation of IIa in
solution is especially fast at elevated temperature.
Chromatographic purification or recrystallization of
IIa from alcohols (MeOH, EtOH, i-PrOH), benzene, or
other solvents results in its complete transformation
into a mixture of compounds V–IX and some others.
We failed to determine whether structure IV is the
only one existing in solution of pyrazolopiperidine IIa
1 For communication IV, see [1].
1157

1158
GUBAIDULLIN et al.
Scheme 1.
Ph
Ph
Ph
O_
N
N
H
N
N
_
O
O
N
N
PhNHNH2
O
O
O
R
N+
N
N+
N
H
H
Alk
Alk
IIa−IIc
IV
Ia−Ic
III
Alk = Me (Ia, IIa), Et (Ib, IIb), Pr (Ic, IIc); R = Me or Et.
Scheme 2.
Ph
Ph
Ph
Ph
Ph
HN
HN
N
N
N
N
N
N
N
N
N
N
N
O
N
N
O
O
O
a/b
O
IIa
+
+
+
+
O
O
N
N
N
Ph
VII
IХ
VI
VIII
V
а, MeOH, 65°C; b, i-PrOH, 80°C.
We succeeded in isolating and unambiguously
identifying 3a,3a′-methylenebis(5-methyl-2-phenyl-
3,3a,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c]pyridin-3-
one) (V) [2, 3], 1-methyl-3-(2-phenylhydrazinylidene)-
pyrrolidin-2-one (VII), and 5-methyl-2-phenyl-3,5,6,7-
tetrahydro-2H-pyrazolo[4,3-c]pyridine (VI) [3–6]. By
NMR spectroscopy we also determined the structure of
methyl 3-(2-phenylhydrazinylidene)-4,5-dihydr-3H-
pyrrole-2-carboxylate (IX) and 3a,5-dimethyl-2-
phenyl-3,3a,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c]-
pyridin-3-one (VIII) [7] (Scheme 2).
among the products. The latter was formed in high
yield, e.g., when pyrazolopiperidine IIa was dissolved
in DMSO. In all cases, the amount of hydrazono-
pyrrolidine VII was considerably smaller. These three
major products were isolated as pure substances and
were extensively studied by spectral methods;
moreover, we succeeded in obtaining their single
crystals suitable for X-ray analysis. Later, we also
succeeded in detecting 3a,5-dimethyl-2-phenyl-
3,3a,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c]pyridin-3-
one (VIII) and methyl (E)-3-(2-phenylhydrazinyl-
idene)-4,5-dihydro-3H-pyrrole-2-carboxylate (IX) [7].
Some other products in such reaction mixtures were
detected only by thin-layer chromatography.
In the reaction of phenylhydrazine with keto ester
Ia (R = Me) under standard conditions of synthesis of
pyrazol-5-ones (heating of the reactants in alcohols or
benzene) we observed formation of a complex mixture
of 5–7 compounds among which no pyrazolopiperidine
IIa was detected [2–6]. When a mixture of Ia and
phenylhydrazine in methanol, propan-2-ol, or benzene
was heated for 5 min under reflux, the products were
compounds V, VI, E isomer of hydrazonopyrrolidine
VII, and some other compounds, but there was no
pyrazolopiperidine IIa. Dihetarylmethane V and
pyrazolotetrahydropyridine VI always predominated
As we showed previously [1, 7], pyrazolopiperidine
IIa is a multident base which forms three hydro-
chlorides X–XII differing by the acid–base ratio:
sesquihydrochloride
X
(2IIa·3HCl), hemihydro-
chloride XI (2IIa·HCl), and dichloride XII
(IIa·2HCl). Hydrochlorides X–XII are stable com-
pounds which can be stored for many years without
appreciable change; however, we failed to isolate free
base IIa from any salt X–XII. In all cases, the
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 84 No. 6 2014

TAUTOMERISM OF AZA HETEROCYCLES: V.
1159
Scheme 3.
Cl_
Me
Ph
H
N+
H
O
O
N
N
H
H
O
O
PHNHNH2
Cl _
H
O
N
N
N+
N+
Me
H
Ph
Me
Ia HCl
ХI
Cl_
H
Me
N+
H
H
Ph
O
Ph
H
N+
N
N+
N
Cl_
H
Cl _
O
PHNHNH2 HCl
HCl
O
Cl _
H
Cl _
N
N+
N+
Me
N+
Me
H
Ph
H
ХII
Х
formation of complex mixtures of products V–IX and
others was observed, and their ratio depended on the
isolation conditions [3, 5–7] (Scheme 3).
X-ray analysis, as well as by a set of one- and two-
1
dimensional NMR correlation techniques (COSY, H–
13C/1H–15N HSQC and HMBC) [8, 9]. The 2D DOSY
and 1D DPFGNOE techniques [10, 11] were applied to
determine the self-diffusion coefficients and nuclear
Overhauser effects (NOE), respectively. The structure
The structure of products V–VII was confirmed by
their elemental compositions, IR and mass spectra, and
(а)
(b)
p
m
δ
calc, ppm
δC
m
o
o
δN
δecp, ppm
Fig. 1. (a) Schematic representation of 1H–13C (gray double-arrowed lines) and 1H–15N couplings (black double-arrowed lines) in the
molecule of dihetarylmethane V and (b) correlations between the calculated and experimental δC and δN values.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 84 No. 6 2014

1160
GUBAIDULLIN et al.
Table 1. Selected bond lengths (Å) in molecules V, VI, and XIIIa
Bond
V1A
V1B
V2A
V2B
VIA
VIB
XIIIb
O3–C3
1.221(2)
1.217(2)
1.213(4)
1.244(5)
1.227(3)
1.226(3)
1.223(2)
N1–N2
N1–C9
N2–C3
N2–C10
N6–C5
N6–C7
N6–C16
C3–C4
C4–C5
C4–C9
C4–C17
C7–C8
C8–C9
1.420(2)
1.276(2)
1.371(2)
1.420(2)
1.460(2)
1.463(2)
1.458(2)
1.516(2)
1.543(2)
1.497(2)
1.541(2)
1.527(3)
1.491(2)
1.421(2)
1.282(2)
1.378(2)
1.417(2)
1.454(2)
1.458(2)
1.460(2)
1.520(2)
1.547(2)
1.495(2)
1.542(2)
1.529(3)
1.487(2)
1.421(4)
1.283(5)
1.362(5)
1.426(5)
1.457(5)
1.454(6)
1.456(5)
1.518(5)
1.560(5)
1.482(5)
1.541(4)
1.526(6)
1.488(6)
1.413(5)
1.301(6)
1.359(5)
1.422(6)
1.460(6)
1.471(6)
1.447(6)
1.489(6)
1.553(6)
1.490(6)
1.526(5)
1.502(8)
1.499(7)
1.406(3)
1.301(3)
1.403(3)
1.408(3)
1.312(3)
1.442(4)
1.466(3)
1.431(3)
1.371(3)
1.405(3)
–
1.408(3)
1.302(4)
1.401(3)
1.407(3)
1.315(3)
1.446(4)
1.460(3)
1.431(3)
1.370(4)
1.402(3)
–
1.417(2)
1.284(2)
1.376(2)
1.416(2)
1.500(2)
1.506(2)
1.499(2)
1.521(3)
1.531(2)
1.500(3)
1.537(3)
1.530(3)
1.487(3)
1.483(5)
1.482(4)
1.401(4)
1.467(4)
a
The bond lengths in the benzene fragments of all compounds are close to reference values. b The N6–H6 bond length in XIII is 1.08(2) Å.
of dihetarylmethane V was established using a series
of homo- and heteronuclear shift correlation
MeOH, EtOH, i-PrOH, MeCN, acetone) and rhombic
V2 (from CH2Cl2), the latter crystallizing in P21212
chiral space group. Asymmetric parts of unit cells of
polymorphs V1 and V2 each contain 1/2 of two
molecules (V1A, V1B and V2A, V2B) which are
located in partial positions on the second-order rotation
axes passing through the bridging carbon atoms. The
molecular structures of both polymorphs of V and their
crystal packings are shown in Figs. 2–5, and their
selected geometric parameters are given in Tables 1–3.
1
1
experiments (1H–1H, H–13C, H–15N; Fig. 1a; trivial
1H–1H COSY and H–13C HSQC correlations are not
1
shown). A good correlation (R2 = 0.99) between the
13
15
calculated (GIAO DFT) and experimental C and N
chemical shifts (Fig. 1b) may be regarded as an
additional evidence in favor of the assumed structure
of V in solution.
Compound V is a dihydric base which reacts with
HCl to produce dihydrochloride V·2HCl. Unlike
pyrazolopiperidine IIa, free base V can be readily
recovered from its dihydrochloride, and the latter can
be stored for many years. The 1H NMR spectra of V in
MeOH and MeOD are more complex than in CCl4, but
removal of methanol leaves unchanged compound V.
Variation of the 1H NMR spectra was also observed for
solutions of V in DMSO-d6. The most stable are
solutions of V in methylene chloride.
All four molecules of two polymorphs turned out to
have the structure of a single tautomer, 3,3a,4,5,6,7-
hexahydro-2H-pyrazolo[4,3-c]pyridin-3-one derivative.
Hydrogen atoms of the C8H2 bridging methylene
group, though constitute the C8–C9=N1 enamine
fragment, are insufficiently acidic to allow formation
of N1H tautomer and the more so zwitterionic
structures. This conclusion is also supported by
analysis of the bond lengths (Table 1). The C3=O3
bond lengths exactly match the double bond (1.217–
1.244 Å; reference data: 1.210 Å [12]) despite the
neighborhood of the C3–N2 amide bond. The length of
Compound V crystallizes from many solvents to
give well-shaped crystals. We isolated two poly-
morphic modifications of V: monoclinic V1 (from
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 84 No. 6 2014

TAUTOMERISM OF AZA HETEROCYCLES: V.
Table 2. Selected bond angles (ω, deg) in molecules V, VI, and XIIIa
1161
Angle
N1N2C3
N1N2C10
N2N1C9
C3N2C10
C5N6C7
C5N6C16
C7N6C16
O3C3N2
O3C3C4
C 2C3C4
C3C4C5
C3C4C9
C3C4C17
C5C4C9
C5C4C17
C9C4C17
N6C5C4
N6C7C8
C7C8C9
N1C9C4
N1C9C8
C4C9C8
N2C10C11
N2C10C15
C4C17C4'
V1A
V1B
V2A
V2B
VIA
VIB
XIIIb
112.3(1)
118.5(1)
106.9(1)
129.1(2)
111.4(1)
109.8(1)
111.3(1)
127.1(1)
127.2(1)
105.7(1)
111.0(1)
100.5(1)
111.5(1)
106.5(1)
109.0(1)
118.1(1)
109.6(1)
111.0(1)
107.9(1)
114.1(1)
124.1(1)
120.3(1)
119.9(1)
120.4(1)
119.8(2)
112.2(1)
118.3(1)
106.9(1)
129.4(1)
111.3(1)
111.0(1)
111.4(1)
126.8(1)
127.7(1)
105.5(1)
112.7(1)
100.6(1)
111.8(1)
106.0(1)
108.0(1)
117.6(1)
109.3(1)
110.5(1)
108.4(1)
114.2(1)
123.8(1)
120.7(1)
119. 8(1)
120.7(1)
119.6(1)
112.8(3)
118.4(3)
106.4(3)
128.7(3)
110.1(3)
109.7(4)
110.8(3)
128.5(3)
126.0(3)
105.5(3)
111.2(3)
100.9(3)
112.4(3)
105.9(3)
108.1(3)
118.1(3)
110.3(3)
111.8(3)
107.4(3)
114.2(3)
123.7(3)
120.5(3)
120.7(4)
120.7(4)
117.3(4)
111.3(3)
117.3(4)
105.8(4)
131.4(4)
110.9(4)
109.8(4)
110.8(5)
124.9(4)
126.2(4)
108.9(4)
111.5(4)
98.8(4)
112.7(2)
118.3(2)
104.6(2)
128.9(2)
121.0(2)
122.0(2)
116.4(2)
125.2(2)
132.1(2)
102.7(2)
131.3(2)
106.7(2)
–
112.5(2)
118.5(2)
104.6(2)
129.0(2)
119.6(2)
123.0(2)
117.3(2)
125.6(2)
131.6(2)
102.9(2)
131.8(2)
106.6(2)
–
112.4(1)
119.0(1)
106.8(2)
127.9(2)
112.2(1)
109.0(1)
110.7(1)
127.3(2)
127.0(2)
105.6(1)
110.9(1)
100.1(1)
109.3(1)
109.6(1)
112.9(1)
113.3(2)
110.9(1)
110.9(1)
107.8(1)
114.2(2)
125.5(2)
119.6(2)
119.6(2)
120.2(2)
–
112.4(4)
106.2(4)
109.2(3)
118.4(4)
109.2(4)
111.9(4)
106.9(4)
115.1(4)
123.1(4)
120.0(4)
119.6(5)
120.3(5)
119.5(5)
121.9(2)
–
121.5(2)
–
–
–
121.3(2)
117.9(2)
112.1(3)
113.3(2)
127.1(2)
119.4(2)
120.1(2)
120.7(2)
–
122.2(2)
121.5(3)
116.1(3)
113.4(2)
127.6(2)
118.9(2)
119.8(2)
121.7(2)
–
a
The bond angles in the benzene fragments of all compounds are close to reference values. b Bond angles in XIII: C5N6H6 107.7(2)°,
C7N6H6 108.6(2)°, C16N6H6 108.4(2)°.
the latter (1.276–1.307 Å) is likely to be largely
determined by conjugation with the C=N bond and
phenyl ring. The two independent molecules of
rhombic polymorph V2 display somewhat larger
difference in the C=O bond lengths, as compared to
monoclinic polymorph V1. The C9=N1, N1–N2, and
N2–C10 bond lengths (Table 1) indicate the existence of
conjugation between these fragments. Although these
bonds constitute a part of the pyrazolone ring, their
parameters are more typical of common phenyl-
hydrazones [13, 14]. The C–C and N–C bond lengths
in the piperidine rings approach those in saturated
heterocycles [12]; only the C8–C9 bonds are slightly
shorter due to their involvement in the enamine
fragment (Table 1). The bond angles in the pyrazole
and piperidine rings of molecules of both polymorphs
of V are similar to the corresponding values for
structurally related heterocycles (Table 2).
Pincer-like molecular conformations of polymorph
V2 almost do not differ in the angles of rotation of the
bicyclic fragments about the bonds connecting them
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 84 No. 6 2014

1162
GUBAIDULLIN et al.
Table 3. Selected torsion angles (φ, deg) in molecules V, VI, and XIII
Angle
V1A
V1B
V2A
V2B
VIA
VIB
XIII
N1N2C3O3
N1N2C3C4
N1N2C10C11
–173.8(1)
6.5(2)
173.3(1)
–7.7(1)
174.1(3)
–4.5(4)
–175.5(4)
2.9(5)
177.5(3)
–2.1(3)
–6.7(3)
172.6(2)
–
179.8(3)
–0.3(3)
–0.5(4)
179.5(2)
–
–171.7(2)
8.8(2)
15.1(2)
–12.8(2)
167.4(1)
120.5(1)
–3.2(2)
–4.9(6)
4.2(7)
16.5(3)
–163.1(2)
–110.8(2)
–0.5(2)
170.1(2)
–123.8(2)
–8.1(2)
111.1(2)
48.9(2)
–78.4(2)
–53.5(2)
–1.3(3)
56.8(3)
172.5(2)
–68.3(2)
–5.6(2)
–153.4(2)
27.0(2)
158.6(2)
5.4(2)
N1N2C10C15 –163.6(2)
175.2(5)
122.7(4)
–2.4(4)
–177.1(5)
–123.0(5)
3.3(5)
N1C9C4C17
N2N1C9C4
N2N1C9C8
N2C3C4C5
N2C3C4C9
N2C3C4C17
N6C5C4C9
N6C5C4C17
N6C7C8C9
O3C3N2C10
O3C3C4C5
O3C3C4C9
О3C3C4C17
C3N2N1C9
–120.3(1)
2.6(2)
0.0(3)
–0.2(3)
179.0(3)
–179.1(2)
0.2(3)
–
168.7(1)
–116.7(1)
–4.5(1)
121.5(1)
54.8(1)
–73.5(1)
–50.3(2)
0.2(3)
–170.4(1)
117.7(1)
5.2(1)
–167.8(4)
114.7(3)
2.8(4)
168.1(5)
–112.2(4)
–0.9(5)
–175.6(3)
179.1(3)
1.9(3)
–120.4(1)
–55.1(1)
71.7(1)
–124.0(3)
–54.9(4)
72.6(4)
124.8(4)
55.1(5)
–
–6.0(4)
–
0.5(4)
–
–73.5(4)
–51.8(6)
3.8(8)
49.6(2)
51.6(5)
–29.7(4)
–6.2(4)
–0.4(5)
–177.6(3)
–
4.3(6)
–0.3(4)
0.8(5)
180.0(3)
–
–2.9(2)
–3.4(6)
63.6(2)
175.8(1)
–58.2(2)
–6.0(2)
–63.3(2)
–175.8(2)
58.6(2)
–63.9(5)
–175.9(3)
57.3(5)
66.2(6)
177.5(4)
–56.8(6)
–3.9(5)
7.1(2)
4.5(4)
1.4(3)
0.3(3)
179.57(2)
–0.3(4)
179.6(2)
0.0(3)
–179.2(3)
–
C3N2C10C11 –160.4(1)
163.2(1)
–16.6(2)
–164.3(1)
–1.2(2)
172.5(5)
–7.4(6)
–175.1(5)
3.6(8)
177.2(2)
–3.5(4)
177.2(3)
–1.3(3)
174.7(3)
–
C3N2C10C15
C3C4C5N6
C3C4C9N1
C3C4C9C8
C3C4C17C4'
C4C3N2C10
C4C5N6C7
C4C5N6C16
C4C17C4'C5'
C5C4C9N1
C5C4C9C8
C5C4C17C4'
C5N6C7C8
C7C8C9N1
C7C8C9C4
C8C7N6C16
20.8(3)
163.3(1)
1.1(2)
–163.6(3)
–0.2(4)
161.7(4)
–1.6(5)
–165.3(1)
–67.2(1)
–177.7(1)
–65.5(1)
170.7(1)
169.9(1)
116.9(1)
–49.7(2)
–175.2(3)
63.1(2)
166.4(1)
56.6(1)
165.8(3)
61.8(2)
–166.9(4)
–60.3(3)
–177.8(5)
–65.5(5)
172.7(4)
175.1(4)
113.9(4)
–51.4(6)
175.1(4)
63.8(6)
–165.7(2)
–
176.1(1)
66.9(1)
178.0(3)
65.0(4)
174.2(2)
–4.7(4)
–175.3(3)
–
179.5(2)
1.4(4)
–179.5(2)
–
179.3(2)
–57.5(2)
179.4(2)
–
–168.3(1)
–178.9(1)
–118.7(2)
48.9(2)
–172.8(3)
–175.3(3)
–116.1(4)
49.9(4)
–178.8(2)
–2.8(4)
–
179.4(3)
0.1(4)
–
122.1(2)
–49.1(2)
–
–178.9(1)
–63.7(2)
119.8(2)
–46.5(2)
171.8(1)
–175.2(3)
–63.5(4)
116.1(4)
–48.5(5)
175.0(4)
23.6(4)
–164.6(3)
20.0(4)
–165.2(2)
–3.9(6)
178.4(4)
–2.4(5)
176.9(4)
60.5(2)
–119.1(2)
50.9(2)
–177.4(2)
–117.6(2)
47.6(2)
–114.3(6)
49.7(6)
–173.9(1)
–174.0(5)
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TAUTOMERISM OF AZA HETEROCYCLES: V.
1163
Table 3. (Contd.)
Angle
V1A
73.3(2)
–6.0(2)
177.8(1)
48.5(1)
V1B
–71.9(2)
7.1(2)
V2A
–71.3(5)
4.5(4)
V2B
71.7(6)
–3.9(5)
176.7(4)
53.6(3)
VIA
–
VIB
–
XIII
С8C9C4C17
C3N2N1C9
C9N1N2C10
C9C4C17C4'
78.1(2)
–5.6(2)
–176.9(2)
–
1.4(3)
0.3(3)
–176.2(1)
–59.1(1)
–177.8(3)
–55.1(3)
–175.4(2) –179.5(2)
–
–
with the bridging CH2 group (C4–C17 and C17–C4' ), but
the corresponding difference for polymorph V1
molecules reaches 10° (Fig. 3, Table 3). The two
independent molecules in both polymorphs are
characterized by the opposite configurations of the C3a
chiral centers (C4B in figures), R,R in one molecule and
S,S in the other, so that crystals of both polymorphs are
racemic compounds.
The pyrazolopiperidine fragments in all molecules
of both polymorphs of V are appreciably bent along
the C4–C9 bond (Figs. 2, 3; Table 3) due to the
presence of bridging methylene group attached to C3a
(C4 in Figs. 2, 3). This configuration considerably
differs from the configuration of strongly flattened
pyrazolopiperidinium cations in previously described
hydrochlorides X–XII and pyrazolotetrahydropyridine
VI, where the C3a atom bears no substituent [1]. As a
result, the piperidine rings in V1 and V2 adopt a
clearly defined chair conformation. The sum of the
bonds angles at the piperidine nitrogen atoms (N6)
ranges within 330.0–335.6°, which corresponds to
fairly high degree of their pyramidality CPN [15] (0.61–
0.74). The C=N carbon atom and pyramidal N6 nitro-
gen atom with equatorial methyl substituent
appreciably deviate from the C4C5C7C8 plane formed
by the other atoms of the piperidine ring (Table 3).
These deviations are as follows: V1: 0.535 (C9A), 0.697
Differences in the conformations of fragments
constituting independent molecules of the two
polymorphs can be clearly demonstrated by super-
position of these molecules as shown in Fig. 3 rather
than by comparison of torsion angles. The two
molecules of V1 differ from each other in both pincer
angle and angles of rotation of the heterocyclic
fragments (Fig. 3a, Table 3), whereas the geometric
structures of both molecules of V2 are virtually similar
(Fig. 3b).
(а)
(b)
Fig. 2. Structures of independent molecules of dihetarylmethane polymorphs (a) V1 and (b) V2 according to the X-ray diffraction
data. Non-hydrogen atoms are shown as thermal vibration ellipsoids with a probability of 30%. Hydrogen atoms in molecule V1 are
not shown.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 84 No. 6 2014

1164
GUBAIDULLIN et al.
(а)
(b)
Fig. 3. Arbitrary superpositions of two independent molecules of dihetarylmethane polymorphs (a) V1 and (b) V2. The two
independent molecules of both polymorphs have opposite configurations, so that one independent molecule is superimposed onto the
inverted second molecule.
(N6A), 0.522 (C9B), 0.703 Å (N6B); V2: 0.535 (C9A),
to N2 is slightly turned about the N2–C10 bond by ~15
(V1A), ~12.8 (V1B), ~6 (V2A), and ~3.5° (V2B)
(Table 3). It is seen that the benzene rings in the
molecules of V1 are turned through a larger angle than
in polymorph V2 molecules. Analogous differences
were also observed in the structure of the cationic parts
of hydrochlorides X–XII [1].
0.702 (N6A), 0.556 (C9B), 0.701 Å (N6B).
The conformation of the pyrazolone rings in all
molecules V may be described as a weakly defined
envelope with planar configuration of bonds at the
amine nitrogen atom (N2). The benzene ring attached
Fig. 5. Double chains formed by molecules of polymorph
V1 via a combination of C–H···O interactions (dotted lines)
and π···π contacts. A view along the 0b crystallographic
axis.
Fig. 4. Intramolecular hydrogen bonds system (dotted lines)
in the molecules of dihetarylmethane V in crystal.
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TAUTOMERISM OF AZA HETEROCYCLES: V.
1165
Table 4. Parameters of intra- and intermolecular contacts in the crystal structures of compounds V–VIII
Comp.
no.
Comp.
no.
∠DHA,
∠DHA,
Hydrogen bond H···A, Å D···A, Å
Hydrogen bond H···A, Å D···A, Å
11A–H11A···N1A 2.44
C11B–H11B···N1B
2.42
C15A–H15A···O3A 2.24
deg
deg
V1
C8AH81A···O3A
2.49
2.59
2.48
2.45
2.39
2.37
2.62
2.63
2.67
2.44
2.48
2.43
2.70
2.30
2.37
2.31
2.65
2.66
2.55
2.70
3.320(3)
3.274(3)
2.804(2)
2.789(2)
2.957(3)
2.950(2)
3.007(2)
3.049(2)
3.498(3)
3.200(7)
3.232(5)
2.785(6)
3.526(9)
2.923(6)
2.736(7)
2.920(6)
3.045(4)
3.046(4)
3.512(5)
3.440(6)
143
128
101
102
119
120
104
106
123
134
134
103
149
124
103
123
105
104
174
135
VI
C
2.773(3)
2.768(4)
2.882(3)
2.905(3)
3.217(3)
3.405(4)
3.184(4)
3.054(2)
2.813(3)
2.953(3)
3.037(2)
3.139(2)
2.933(3)
3.633(2)
3.305(3)
3.462(3)
101
C8B–H82B···O3B
C11A–H11A···N1A
C11B–H11B···N1B
C15A–H15A···O3A
C15B–H15B···O3B
C17B–H173B···N6B
C17A–H171A···N6A
С7B–H71B···O3A а
C8B–H81B···O3B
C8A–H82A···O3A
C11A–H11A···N1A
C14А–Н14А···O3В
C15A–H15A···O3A
C11B–H11B···N1B
C15B–H15B···O3B
C17B–H173B···N6B
C17A–H171A···N6A
C7A–H71A···O3А b
C16A–H161···O3B c
102
126
C15B–H15B···O3B
C5A–H5A···O3B d
2.27
125
2.38
150
C16A–H161A···O3B d 2.59
C14B–H14B···O3A e 2.47
143
134
VII
N2–H2···O3
2.19
167
VIII C11–H11···N1
C15–H15···O3
2.49
100
V2
2.40
117
N6–H6···Cl1
2.04(3)
2.08(3)
1.96(2)
2.71
153(3)
171(3)
175(3)
156
O11–H111···Cl1
O11–H112···O3 f
C5–H51···Cl1 f
C7–H71···O11 g
C16–H161···O3 h
2.49
140
2.56
153
a
b
c
d
e
Symmetry operations: x, 1 – y, 1/2 + z. 3/2 – x, –1/2 + y, 1 – z. 1/2 + x, 1/2 – y, 1 – z. –x, 1/2 + y, 1/2 – z. –x, –1/2 + y, 1/2 – z.
f 1 – x, 2 – y, 1 – z. g 1 – x, –1/2 + y, 3/2 – z. h 1 – x, 1/2 + y, 3/2 – z.
Intra- and intermolecular interactions in both
are considerably different in molecules A and B of
polymorphs V1 and V2: 5.112(3) and 6.563(2) Å in
V1A and V1B and 5.964(4) and 5.643(4) Å in V2A
and V2B, respectively.
polymorphs of V include mainly hydrogen bonds like
C–H···N and C–H···O (Table 4), as well as intra-
molecular π···π contacts between the five-membered
rings (Table 5). Taking into account structural
similarity of molecules VA and VB, it should be
emphasized that the modes of intramolecular hydrogen
bonding are identical for in all molecules of V (Fig. 4)
with an accuracy of 1/2 molecule (independent part).
The supramolecular structure of polymorph V1 is
determined by a combination of three types of
intermolecular interactions. Hydrogen bonds C–H···O
involving the O3A carbonyl oxygen atom of V1A give
rise to chains consisting of alternating molecules A and
B along the 0c crystallographic axis (Table 4). Two
neighboring chains are linked to each other through
π···π contacts between the aromatic substituents with
an intercentroid distance of 4.837(3) Å, dihedral angle
of 0°, and shortest interplanar distance of 3.29 Å
(Fig. 5).
As seen from the data in Table 5, π···π contacts
with similar parameters exist between the five-mem-
bered rings in molecules of both polymorphs. Pre-
sumably, these contacts provide additional stabilization
of the pincer conformation. The distances between the
centroids of the phenyl rings are much longer, and they
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 84 No. 6 2014

1166
GUBAIDULLIN et al.
Table 5. Parameters of π···π and CH···π contacts involving the five-membered rings in the crystal structures of compounds
V, VII, and XIII [30]a
Compound no.
V1A
Contact
Cg···Cg'
d1
d2
3.063
3.032
3.038
3.072
3.21
–
α
β
3.128(2)
3.081(2)
3.083(2)
3.133(3)
5.279(2)
2.86
18.42
16.75
19.75
22.55
0.0
11.76
10.21
9.90
11.30
52.5
–
V1B
Cg···Cg'
V2A
Cg···Cg'
V2B
Cg···Cg'
Cg···Cg b
C3–H31···Cg2 c
C1–H103···Cg2 d
C3–H31···Cg e
C1–H103···Cg f
VII
140
2.84
–
158
140
158
–
XIII
2.86
–
–
2.84
–
–
a
d1 is the distance between the centroids of rings (Cg), Å; d2 is the shortest distance between the ring planes, Å; α is the dihedral angle
between the ring planes, deg; and β is the ring overlap angle, deg. Symmetry operations: b 1 – x, –y, –z. c x, 1/2 – y, 1/2 + z. d –x, –y, 1 – z.
e x, 1/2 – y, 1/2 + z. f –x, –y, 1 – z.
The third type of interactions is responsible for
each other to produce a zigzag band with outer
hydrophobic margins composed of phenyl substituents
(Fig. 8a). The O3B atoms are also involved in
bifurcated hydrogen bonds which combine similar
bands with formation of a two-dimensional system, a
corrugated bilayer consisting of H-bonded molecules,
which is parallel to the a0b crystallographic plane and
bounded at the outer sides by phenyl substituents
(Table 5). The reason is that molecules A and B in the
H-dimer are turned relative to each other through an
angle of 90°, and the two terminal hydrogen bonds
appear mutually orthogonal (Fig. 8b).
binding of similar neighboring double chains. This
interaction comprises exclusively “jamming” of
bridging methylene groups between two phenyl
substituents of molecules belonging to neighboring
double chains. It may be clearly illustrated by two
projections of crystal packing of polymorph V1 shown
in Fig. 6. As a result, a layer is formed from the
parallel double chains in the a0c plane (Fig. 6). On the
whole, the crystal packing of V1 may be represented as
parallel laying of similar laminar structures shown in
Fig. 6 along the 0b crystallographic axis. Interactions
between such layers involve only conventional van der
Waals contacts. Despite relatively low crystal packing
factor (65.8%), unit cells possess no voids capable of
accommodating solvent molecules.
The outer sides of the H-bonded bilayer (Fig. 8) are
composed of molecules V2B that are (R,R)-
stereoisomers. The inner part consists of (S,S)-isomeric
molecules V2A, i.e., both enantiomers in crystal are
spatially separated. This suggests to some extent the
ability of racemic compound V2 to undergo
spontaneous resolution. Further development of the
crystal packing of V2 involves exclusively π···π (like
T-stacking) and C–H···π contacts between molecules
B belonging to neighboring bilayers, so that the
corrugated bilayers are linked along the 0c
crystallographic axis. Here, the C–H···O interactions
are observed only with outer molecules V2B within a
corrugated bilayer. However, the calculated packing
factor (64.3%) turned out to be even lower than those
typical of crystalline organic compounds (65–75%)
[16].
No intermolecular π···π contacts is observed in
rhombic polymorph V2, and intermolecular inter-
actions are represented mainly by pair C–H···O
hydrogen bonds. The two independent molecules of
V2, being conformationally identical (with opposite
configurations of the chiral atom; Fig. 3), have
different molecular environments and are involved in
different interactions. The supramolecular structure of
V2 is characterized by formation of V2A···V2B head-
to-head hydrogen-bonded dimers (Fig. 7). These
dimers are formed with participation of only O3B
carbonyl oxygen atoms of molecules V2B, whereas the
O3A atoms in molecules V2A link the H-dimers with
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 84 No. 6 2014

TAUTOMERISM OF AZA HETEROCYCLES: V.
1167
(а)
(b)
Fig. 6. Projections along the (a) 0a and (b) 0c axes of crystal packing of polymorph V1. Hydrogen bonds are shown with dotted lines;
methylene groups in molecules belonging to neighboring bilayers are also shown as van der Waals spheres.
Fig. 7. Hydrogen-bonded dimer formed by molecules A and B of rhombic polymorph V2. Hydrogen bonds are shown with dotted
lines.
Pyrazolotetrahydropyridine VI was initially
isolated by chromatography from the complex mixture
of products obtained in the reaction of
phenylhydrazine with keto ester Ia with a view to
synthesize pyrazolopiperidine IIa [3]. The structure of
VI was assigned on the basis of spectral data. Unlike
The structure of compound VI in crystal was also
determined by X-ray analysis (Fig. 10); single crystals
were obtained by crystallization from acetone. Like
compound V, the independent part of the unit cell of
VI contains two molecules VIA and VIB. The
geometric parameters are given in Tables 1–3, and the
molecular structures are shown in Fig. 10. Figure 11
shows an arbitrary superposition of two independent
molecules VIA and VIB, which reveals different
conformations of the tetrahydropyridine fragments
therein and some difference in the rotation of the
phenyl substituent with respect to the five-membered
ring plane.
1
compound V, the H NMR spectrum of VI in CDCl3
contained a singlet at δ 7.71 s (1H, 4-H), and the
intensity of the CH2 signals was lower. Compound VI
displayed in the IR spectrum absorption bands due to
stretching vibrations of aromatic C=C bonds
(1593 cm–1), carbonyl absorption band at 1663 cm–1
(which was displaced to lower frequencies due to
conjugation), and a very strong band at 1626 cm–1,
which is likely to originate from stretching vibrations
of the conjugated bond system in the heterocyclic
fragment. This assumption is confirmed by a good
agreement between the experimental and calculated
The C5–N6 bonds in the tetrahydropyridine rings of
VIA and VIB (1.312–1.315 Å) are appreciably shorter
than the other C–N6 bonds (1.446–1.464 Å), which
was not observed in polymorphs V1 and V2. Despite
the presence of contiguous C4=C5 double bond and
shortening of the neighboring C3–C4 bond to ~1.430 Å,
the C3=O3 carbonyl bond length in both molecules of
13
15N and C chemical shifts in the NMR spectra of VI
(an example of such correlation for carbon chemical
shifts is shown in Fig. 9; R2 = 0.999).
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1168
GUBAIDULLIN et al.
(а)
(b)
Fig. 8. Projections along the (a) 0b and (b) 0c axes of a corrugated bilayer formed by hydrogen-bonded molecules of polymorph V2
(C–H···O hydrogen bonds are shown with dotted lines).
VI is the same as in all molecules of V (Table 1). It
should be noted that, despite similarity of the C7–N6
bond lengths in molecules of both compounds, the
C7–C8 bonds in VI are slightly shorter and different in
independent molecules VIA and VIB [1.483(5) and
1.401(4) Å, respectively].
The presence of a C4=C5–N6 enamine bond system
makes the tetrahydropyridine ring in VI flattened
(Table 3, Fig. 11); as a result, the entire pyrazolo-
pyridine fragment becomes flatter: the dihedral angle
between the five-membered ring and the C9C4C5N6C7
fragment is as small as ~5°. The configuration of
bonds on the amino nitrogen atom (N6) is planar due to
conjugation in the enamine fragment (the sum of the
bond angles on the N6 nitrogen atom approaches 360°,
Table 2).
δСcalc, ppm
The benzene rings in VIA and VIB are turned
about the N2–C10 bond through a smaller angle (~3.5
and 0.5°, respectively) than in polymorph V1, and
these angles are close to those found for V2A and V2B
(Table 3). This leads to strengthening of the
intramolecular hydrogen bonds C15–N15···O3 and
C11–H11 ···N1 and hence shortening of the C15···O3 and
C11 ···N1 distances and increase of the C15N15O3 and
C11H11N1 angles (Table 4).
δСexp, ppm
The supramolecular structure of compound VI in
crystal is also determined by only C–H···O and
C–H···N hydrogen bonds, while classical hydrogen
bonds are lacking. The C–H···O bonds link molecules
Fig. 9. Correlation of the experimental (CDCl3) and
calculated 13C chemical shifts of pyrazolotetrahydropyridine
VI.
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TAUTOMERISM OF AZA HETEROCYCLES: V.
1169
Fig. 10. Structures of independent pyrazolotetrahydropyridine molecules VIA and VIB according to the X-ray diffraction data. Non-
hydrogen atoms are shown as thermal vibration ellipsoids with a probability of 50%, and hydrogen atoms are shown as spheres with
an arbitrary radius.
Fig. 11. Arbitrary superposition of two independent pyrazolotetrahydropyridine molecules VIA and VIB.
VIA and VIB to dimers, and the C–H···N bonds give
rise to H-tetramer (Fig. 12a). The H-dimers are linked
to the H-tetramer only through the N2 atom of one
independent molecule (VIA). We believe that such H-
tetramer formed by a combination of C–H···O and C–
H···N hydrogen bonds should be regarded as a
supramolecular synthon. The H-tetramers are linked to
each other via bifurcated hydrogen bond involving the
O3A atom to produce skewed stacks of molecules
arranged antiparallel to each other (Fig. 12b).
with published data [17], we determined its molecular
geometry in crystal by X-ray analysis. The
independent part of a unit cell of VII includes one
molecule whose structure is shown in Fig. 13, and the
crystal packing, in Fig. 14. The bond lengths and bond
angles in the benzene ring and hydrazone fragment are
typical of phenyl groups with an electron-donating
substituent, such as phenylhydrazones [13, 14].
Molecules VII in crystal are linked through N–
H···O hydrogen bonds to form a flat band along the 0a
crystallographic axis (Fig. 14a, Table 4). The H-
bonded bands are packed parallel to the a0c
crystallographic plane (Fig. 14b) via a combination of
C–H···π and π···π contacts between the bands (Table
5). Such arrangement of molecules in crystal ensures
their tight packing (the calculated packing factor is
70.7%). Even tighter packing and formation of
additional π···π contacts are hampered by the
methylene and methyl groups which appear just under
the aromatic fragments of neighboring molecules thus
preventing them from approaching each other to a
shorter distance. This parallel packing of molecules
VII in crystal leads to considerable anisometry of the
We succeeded in isolating a small amount of pure
hydrazonopyrrolidine VII together with compounds V
and VI by treatment of sesquihydrochloride X with
potassium carbonate in methanol. Hydrazone VII in
crystal and in solution (DMSO-d6) exists as a single E
isomer (Fig. 13), while in CDCl3 a mixture of
approximately equal amounts of the Z and E isomers is
formed. Presumably, the E/Z isomerization is promoted
by CDCl3. 1-Methyl-3-(2-phenylhydrazinylidene)pyr-
rolidin-2-one (VII) was synthesized previously by
reaction of benzenediazonium salt with 2-chloro-1-
methyldihydropyrrolium chloride [17]. Although the
properties of compound VII isolated by us coincided
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GUBAIDULLIN et al.
(а)
(b)
Fig. 12. (a) Structure of the hydrogen-bonded tetramer formed by pyrazolotetrahydropyridine molecules VIA and VIB and (b) its
crystal packing; hydrogen bonds are shown with dotted lines.
crystal structure, and it may be responsible for aniso-
20°C was heated in boiling methanol for 4 h, we
isolated compounds V and VI and a yellow oily
tropic properties of crystalline compound VII.
1
substance. According to the H, 13C, and 15N NMR
Depending on the conditions of synthesis of
pyrazolopiperidine IIa, purification method, or solvent
nature, the composition of its transformation products
strongly varies. For example, dissolution of IIa in
DMSO leads to formation of pyrazolotetrahyd-
ropyridine VI in a very high yield. The reaction of
phenylhydrazine with keto esters I (R = Me, Et) in
boiling alcohols or benzene gives mainly compounds
V–VII. When pyrazolopiperidine IIa prepared at 15–
data, the latter contained approximately equal amounts
of 3a,5-dimethyl-2-phenyl-3,3a,4,5,6,7-hexahydro-2H-
pyrazolo[4,3-c]pyridin-3-one (VIII) and methyl 3-(2-
phenylhydrazinylidene)-4,5-dihydro-3H-pyrrole-2-car-
boxylate (IX).
We failed to separate oily mixture VIII/IX into
individual components, and their structure was
analyzed by NMR spectroscopy of their mixture.
Signals of particular compounds VIII and IX in the 1H
NMR spectra (CDCl3) were identified using the DOSY
technique due to appreciable difference in their self-
diffusion coefficients, 1.32×10–9 and 1.06×10–9 m2/s,
respectively. Their structure was determined with the
aid of various homo- and heteronuclear shift
1
correlation techniques (COSY, H–13C/1H–15N HSQC
and HMBC). The assignment made was additionally
confirmed by a good agreement between the calculated
(DFT GIAO) and experimental 13C and 15N chemical
shifts; the correlation for compound VIII is given in
Fig. 15 (R2 = 0.999).
Apart from structure assignment, the NMR data
allowed us to refine isomer compositions of
phenylhydrazones VII and IX in solution. According
to the NOE data and the calculated and experimental
13C and 15N chemical shifts, phenylhydrazone VII in
DMSO-d6 exists exclusively as E isomer, whereas in
CDCl3 a mixture of E and Z isomers is formed, the E
isomer prevailing (Fig. 16). By contrast, the NOE
observed between the NH and 4-H protons led us to
conclude that phenylhydrazone IX in DMSO-d6 and
CDCl3 has solely E configuration (Scheme 4).
Fig. 13. Structure of the molecule of phenylhydrazono-
pyrrolidine VII in crystal according to the X-ray diffraction
data. Non-hydrogen atoms are shown as thermal vibration
ellipsoids with a probability of 50%, and hydrogen atoms are
shown as spheres with an arbitrary radius. Selected
geometric parameters (bond lengths and bond and torsion
angles): N1–C4 1.285(3), N1–N2 1.356(3), N2–H2 0.88(3),
N2–C10 1.380(3), O3–C5 1.233(3), C4–C5 1.477(4), C5–N6
1.349(3) Å; N2N1C4 116.6(2)°, N1N2C10 119.9(2)°, N1N2H2
122(1)°, O3C5N6 125.1(2)°, O3C5C4 128.4(2)°, N1C4C5 121.3(2)°,
N1C4C3 129.0(2)°, N2C10C11 119.0(2)°, C5N6C1 125.6(2)°,
C1N6C2 119.4(2)°; C4N1N2C10 177.6(2)°, N1C4C5O3 3.1(4)°,
N1N2C10C11 179.6(2)°.
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TAUTOMERISM OF AZA HETEROCYCLES: V.
1171
(а)
(b)
Fig. 14. (a) Intermolecular hydrogen bonds and (b) crystal packing of hydrazone VII; C–H···π and π···π contacts and N–H···O
hydrogen bonds are shown with dotted lines. Views along the (a) 0b and (b) 0a crystallographic axes.
3a-Methyl derivative VIII forms stable hydro-
chloride XIII which was isolated as monohydrate. Its
structure was determined by X-ray analysis. Hydro-
chloride VIII·HCl·H2O crystallizes in monoclinic
crystal system (space group P21/c) with one indepen-
dent molecule in the asymmetric part of the unit cell.
The structure of hydrochloride XIII is shown in Fig.
17, its geometric parameters are given in Tables 1–3,
and intramolecular hydrogen bonds and intermolecular
contacts are presented in Tables 4 and 5.
rings in XIII, there exist hydrogen bonds C15–H15···O3
and C11–H11···N1 (Table 4), as was observed in the
molecules of V, VI (Table 4), and hydrochlorides X–
XII [1].
Analysis of intermolecular interactions in the
crystal structure of hydrochloride XIII revealed the
presence of various hydrogen bonds, as well as of
C–H···π contacts (Tables 4, 5). Conventional O–
H···O hydrogen bonds involving the O3 carbonyl
oxygen atom hold together the hydration water
molecule and the cation of XIII. The chloride ion in
turn is linked to both the cation through the N6–H···Cl
bond and with the water molecule through the
O–H···Cl bond. A combination of the above
interactions leads to the formation of pseudo-hexamers
consisting of two protonated molecules VIII, two
water molecules, and two chloride ions (Fig. 18).
The O11 oxygen atom (water molecule) also parti-
cipates in bifurcated C–H···O hydrogen bonds with
H71 and H52 in the piperidine methylene groups.
Analogous hydrogen bonds are also observed between
the methyl hydrogen (H161) and O3 carbonyl oxygen
atom and between H14 in the benzene ring and O3 of
the symmetry-related molecule. The C–H···Cl
The conformation of the pyrazolopiperidine frag-
ment in the cationic part of XIII is the same as in
molecules V. It is bent along the C4–C9 bond (Fig. 17;
Tables 2, 3). The bond angles and bond angles therein
are closer to those found for polymorphs V1 and V2
than to the corresponding values for tetrahydropyridine
molecule VI. Only the bonds formed by the N6 atom
with carbons are longer than those in V and VI (Table 1).
As in molecules V and VI, the benzene ring in the
cation of XIII is turned about the N2–C10 bond with
respect to the pyrazolone ring plane through an angle
of ~16.5° which is slightly larger than the
corresponding angle in molecules V1 (Table 3).
Despite acoplanarity of the benzene and pyrazolone
Scheme 4.
Ph
N H
Ph
N
Ph
N
Ph
N
H
N
N
N
H
H
N
O
O
O
O
O
O
N
N
N
N
E-IХ
Z-VII
E-VII
Z-IХ
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1172
GUBAIDULLIN et al.
δСcalc, ppm
δСcalc, ppm
R2 = 0.996
R2 = 0.999
0
40
80
120 160
0
40
80
120
160
200
δСexp, ppm
δСexp, ppm
Fig. 16. Correlation between the experimental (CDCl3) and
calculated 13C chemical shifts of the E (rhombs) and Z
isomers (asterisks) of phenylhydrazone VII.
Fig. 15. Correlation between the experimental (CDCl3) and
calculated 13C chemical shifts of compound VIII.
1
13
hydrogen bonds with Cl1 involve H51 of the piperidine
ring and H163 and H171 methyl hydrogens. These C–
H···O and C–H···Cl hydrogen bonds link pseudo-
hexamers of XIII to produce three-dimensional
network (Fig. 19) with water molecules and chloride
ions located in the pseudochannels, though there is no
direct contact between water molecules or chloride
ions in the channels.
In a few hours after dissolution, the H and C NMR
spectra of IIa in DMSO-d6 contained signals typical of
pyrazolotetrahydropyridine VI. After two days, the
fraction of VI in solution attained ~85%. Oxidation
processes also occurred in solutions of IIa in nonpolar
solvents (PhH, CHCl3, CH2Cl2, etc.) on storage, but
different reactions clearly dominated.
We presumed in [3] that dihetarylmethane (V) is
formed from pyrazolopiperidine IIa and formaldehyde
which can be generated in the reaction mixture from
methanol. The latter was used as solvent or it may
The three-dimensional network (Fig. 19) is
additionally stabilized by C–H···π contacts between
C8H81 and benzene ring: the shortest distance from the
H81 hydrogen atom and the corresponding centroid is
2.80 Å, and the dihedral angle is 127°. No π···π
contacts were observed in the crystal structure of
hydrochloride XIII, presumably due to steric
hindrances originating from the conformation of the
bicyclic system. Despite unfavorable conformations of
the heterocyclic fragment and the whole molecule, the
presence of anions and hydration water molecules
ensures a fairly high packing factor (71.8%) due to the
absence of additional voids potentially accessible to
solvent molecules.
It is difficult to unambiguously interpret pathways
of the transformation of pyrazolopiperidine IIa into
compounds V–IX. Presumably, these reactions involve
one-step, consecutive, and interrelated processes. The
former assumption [3, 5] according to which pyrazolo-
tetrahydropyridine VI is formed via autooxidation of
pyrazolopiperidine IIa was confirmed experimentally.
Fig. 17. Structure of the molecule of hydrated hydrochloride
XIII (VIII·HCl·H2O) in crystal according to the X-ray
diffraction data. Non-hydrogen atoms are shown as thermal
vibration ellipsoids with a probability of 50%, and hydrogen
atoms are shown as spheres with an arbitrary radius.
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TAUTOMERISM OF AZA HETEROCYCLES: V.
1173
Fig. 18. Pseudohexamers formed in the crystal structure of hydrochloride hydrate XIII via hydrogen bonds (dotted lines) with water
molecules.
originate from the methoxycarbonyl fragment of the
initial keto ester (Ia, R = Me). In fact, addition of
formaldehyde to the reaction mixture and even to the
mother liquors increases the yield of V. However, the
reaction with keto ester Ib (R = Et) in both methanol
and ethanol gave the same product rather than the
corresponding 1,1-dihetarylethane derivative. Later,
we detected compound VIII among the transformation
products of IIa in boiling methanol and presumed
possible addition of VIII to the double bond of
pyrazolotetrahydropyridine VI with formation of
dihetarylmethane V. However, this assumption has not
been proved so far. After heating of a mixture of
pyrazolotetrahydropyridine VI and mixture VIII/IX in
methanol, no dihetarylmethane V was detected by
TLC, though initial compound VI was also absent in
the reaction mixture.
derivative VIII and demethylated compound IX. The
alkylation of 5-acetyl-hexahydropyrazolo[4,3-c]pyri-
dines at the N1 or bridgehead C3a atom was reported in
[23]. 3a-Methyl derivative VIII could be formed via
both autoalkylation of initial pyrazolopiperidine IIa at
the C3a atom of the enol form and alkylation of
pyrazolotetrahydropyridine VI possessing an enamine
fragment.
Analysis of published data revealed the ability of
piperidine [18, 19], 4-oxopiperidine [20], and 4-
iminopiperidine derivatives, including those fused to
aza cycles [21, 22], to undergo various transformations
such as ring contraction reactions. These transforma-
tions may involve formation of carbonyl compounds in
which the carbonyl carbon atom was formerly a part of
the piperidine ring [20]. The presence of a quaternary
nitrogen atom strongly facilitates such reactions
(Hofmann degradation, etc.) [18]. It is well known that
quaternary ammonium salts are capable of alkylating
various organic compounds. The above processes may
be responsible for the formation of 3a-methyl
Fig. 19. A fragment of the three-dimensional network
formed in the crystal structure of hydrochloride hydrate XIII
via hydrogen bonds of various types.
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1174
GUBAIDULLIN et al.
Although zwitterionic structures III and IV should
fragment and opening of the other and even more so
with loss of a C2H2 fragment. However, assuming
active participation of oxygen and water, as was noted
for analogous processes [20], the following hypothetic
scheme may be supposed.
favor alkylation and ring contraction processes in
pyrazolopiperidine IIa, it is quite difficult to propose a
feasible scheme for the formation of phenylhydrazones
VII and IX with account taken of recyclization of one
Ph
Ph
N
N
N
N
[O]
OH
OH
IIa
IV
H2C
O
+
[O]
N
[O]
N+
[O]
O_
IIa
IV
VI
NHPh
OH
IV
VIII
N
H2O
IIa
VIII
H2C
O
+
VII
V
OH
VI
N
The different stabilities of previously described 5-
acyl, 5-aryl, 5-(pyridinylmethyl), and even benzyl
derivatives of 3,3a,4,5,6,7-hexahydro-2H-pyrazolo-
[4,3-c]pyridin-3-one [24] and 5-alkyl-2-aryl deriva-
tives synthesized by us are likely to be related to
different basicity centers in their molecules. Intro-
duction of such acceptor groups as acyl, aryl, or
pyridinylmethyl strongly reduces the basicity of the
piperidine nitrogen atom (or makes the other center
more basic), so that the formation of zwitterionic
structure like III or IV becomes improbable. We
believe that the absence of quaternary ammonium
group reduces the probability for analogous trans-
formations of 5-acyl-, 5-aryl-, and 5-(pyridinyl-
methyl)-3,3a,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c]-
pyridin-3-ones.
The X-ray diffraction data for single crystals of
compounds V–VII and XIII were obtained at the Joint
Spectral and Analytical Center for Physicochemical
Studies of Structure, Properties, and Composition of
Substances and Materials of the Arbuzov Institute of
Organic and Physical Chemistry. Experiments were
carried out on a NONIUS B.V. CAD-4 automated
diffractometer (20°C, CuKα radiation, λ 1.54184 Å,
graphite monochromator) for V1 and on a Bruker
Smart Apex II CCD automatic diffractometer (MoKα
radiation, λ 0.71073 Å, graphite monochromator) at
23°C for V2, VI, and VII and at –123°C for XIII. No
reduction of intensity of control reflections was
observed during the data acquisition, and corresctions
for absorption were applied. All the examined
compounds formed colorless prismatic crystals in
rhombic (V2) or monoclinic crystal system (all other
compounds). Table 6 contains the crystallographic
parameters of V–VII and XIII and parameters of X-
ray diffraction experiments and structure refinement.
Selected geometric parameters of molecules V–VII
and XIII are given in Tables 2 and 3.
EXPERIMENTAL
1
The H and 13C NMR spectra were recorded on
Bruker Avance-600 (600 MHz) and Avance-400
1
spectrometers (400 MHz for H) using the solvent
signals as reference. The IR spectra were measured on
a Bruker Vector-22 instrument from samples dispersed
in mineral oil or pelleted with KBr (the difference in
the position of bands did not exceed 1–2 cm–1). The
melting points were determined on Boetius PTP
melting point apparatuses. The mass spectra (electron
impact) were obtained on a Finnigan Trace MS
instrument.
The structures were solved by the direct method
using SIR [25] and SHELXS [26] and were refined ny
the least-squares procedure first in isotropic and then
in anisotropic approximation using SHELXL [26].
Hydrogen atoms in the amino groups and water
molecule were visualized from the difference electron
density maps, and their positions were refined in
isotropic approximation. The coordinates of the other
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TAUTOMERISM OF AZA HETEROCYCLES: V.
1175
Table 6. Crystallographic parameters of compounds V–VII and XIII and conditions of X-ray diffraction experiments
Parameter
Space group
V1
V2
VI
VII
XIII
C 2/c
P21212
P 21/c
P 21/c
Р 21/с
Formula
C27H30N6O2
C27H30N6O2
C13H13N3O
C11 H13N3O C14H18N3O+· Cl– H2O
Unit cell parameters
a 22.865(8)
b 17.586(8 )
a 11.670(1)
b 12.354(1)
a 10.4945(3)
b 10.1283(3)
a 6.516(2)
b 13.521(4)
a 11.964(2)
b 11.175(2)
c 16.531(6) Å c 17.486(1) Å c 21.3515(7) Å c 11.582(3) Å
c 11.628(2) Å
β 111.067(2)°
β 131.72(3)°
4962(3)
8
β 95.000(2)°
2260.9(1)
8
β 94.477(3)°
1017.4(5)
4
Unit cell volume, Å3
2520.8(4)
4
1450.8(4)
4
Z
M
470.57
1.260
470.57
1.240
227.26
1.335
203.24
1.327
297.78
1.363
d
calc, g/cm3
Absorption coefficient, cm–1
6.60
0.81
0.88
0.89
2.69
F(000)
2000
1000
960
432
632
X-Ray radiation, λ, Å
θ range
1.54184
3.61–74.19
0.71073
2.85–27.97
0.71073
2.61–32.05
0.71073
2.32–28.41
0.71073
1.82–28.80
hkl ranges
0 ≤ h ≤ 28,
0 ≤ k ≤ 21,
–20 ≤ l ≤ 15
5141
–15 ≤ h ≤ 15,
–14 ≤ k ≤ 16,
–22 ≤ l ≤ 22
18726
–14 ≤ h ≤ 14,
–12 ≤ k ≤ 15,
–29 ≤ l ≤ 26
11454
–8 ≤ h ≤ 8,
–17 ≤ k ≤ 17,
–15 ≤ l ≤ 15
8833
–16 ≤ h ≤ 15,
–15 ≤ k ≤ 14,
–15 ≤ l ≤ 15
21353
Total number of reflections
Rint
0.0467
4138
0.0949
2695
0.0225
3553
0.0647
891
0.0380
2946
Number of independent
reflections with I > 2σ(I)
Divergence factors for reflections
with I > 2σ(I)
R 0.0425,
Rw 0.1192
1.008
R 0.0744,
Rw 0.1803
0.958
R 0.0745,
Rw 0.2012
1.036
R 0.0576,
Rw 0.1286
0.915
R 0.0543,
Rw 0.1305
1.047
Goodness of fit
Number of variables
318
317
303
141
192
Maximum and minimum residual
0.204,
–0.140
0.544,
–0.176
0.782,
–0.680
0.148,
–0.181
0.449,
–0.363
electron density peaks, ē/Å3
hydrogen atoms were calculated on the basis of stereo-
chemical considerations and were refined according to
the riding model.
the Cambridge Crystallographic Data Centre (entry
nos. CCDC 942105–942109, respectively).
3a,3a′-Methylenebis(5-methyl-2-phenyl-3,3a,4,5,6,7-
hexahydro-2H-pyrazolo[4,5-c]pyridin-3-one) (V).
a. A mixture of 5.0 g (0.292 mol) of methyl 1-methyl-
The data were acquired and edited, and the unit cell
parameters were refined with the aid of MolEN [27]
and APEX2 packages [28]. All calculations were
performed using WinGX [29], intermolecular
interactions were analyzed by PLATON [30], and the
molecular structures were plotted using Mercury [31].
4-oxopiperidine-3-carboxylate (Ia) and 3.16
g
(0.292 mol) of freshly distilled phenylhydrazine in
25 mL of methanol was heated for 10 min under reflux
and was then left overnight at room temperature. The
precipitate was filtered off and washed on a filter with
cold methanol to isolate 1.9 g (27.6%) of V as color-
The coordinates of atoms in structures V–VII and
XIII and their temperature factors were deposited to
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1176
GUBAIDULLIN et al.
less crystals. Recrystallization from carbon tetra-
chloride gave fine colorless crystals with mp 189–191°C
(decomp., PTP), 185–188°C (decomp., Boetius). In
both cases recrystallization was observed in the tem-
perature range from 162 to 168°C. The product is
soluble in acetone, DMSO, MeCN, and CH2Cl2, and
poorly soluble in CCl4. Samples of V obtained by
recrystallization from CCl4, MeOH, i-PrOH, acetone,
or MeCN had identical IR spectra. IR spectrum (KBr),
ν, cm–1: 3065, 2972, 2942, 2894, 2856, 2789, 2716,
1698, 1688, 1619, 1596, 1497, 1453, 1392, 1366,
1347, 1285, 1251, 1213, 1197, 1171, 1135, 1114, 1088,
5.88; Cl 12.81; N 15.29. C27H30N6O2·2HCl. Cal-
culated, %: C 59.67; H 5.93; Cl 13.05; N 15.46.
5-Methyl-2-phenyl-3,5,6,7-tetrahydro-2H-pyra-
zolo[4,5-c]pyridin-3-one (VI). A mixture of 2.0 g of
pyrazolopiperidine IIa and 50 mL of anhydrous
propan-2-ol was heated under reflux until complete
dissolution. The solution was filtered while hot and
was left to stand for 3 days at room temperature. The
crystals were filtered off, washed with propan-2-ol,
and dried. According to the IR and TLC data, the
product (0.75 g, white fine crystals) was compound V.
The mother liquor was evaporated under reduced
pressure, and the residue, a dark thick oily material,
was dissolved in a minimum amount of acetone. The
solution was left overnight, and the crystals were
filtered off and recrystallized once more from acetone.
Yield of VI 0.15 g (7.6%), light brown needles, mp
197–198°C (decomp.). IR spectrum (KBr), ν, cm–1:
3115, 3038, 2963, 2852, 2808, 1662, 1620, 1593,
1556, 1523, 1488, 1457, 1432, 1415, 1349,1326, 1249,
1
1038, etc. H NMR spectrum (CCl4), δ, ppm (J, Hz):
3
3
7.20 d (4H, o-H, J = 8.0), 6.85 t (4H, m-H, J = 8.0),
3
6.69 t (2H, p-H, J = 8.0), 2.58–2.74 m (8H, 4-Heq, 6-
Heq, 7-Heq, 3a-CH2), 2.01 m (2H, 4-Hax), 1.99 s (6H,
13
NMe), 1.61 m (2H, 6-Hax, 7-Hax). C NMR spectrum
(CCl4), δC, ppm: 172.23 (C=O), 162.79 (C=N), 137.70
(Ci), 127.98 (Cm), 124.03 (Cp), 118.03 (Co), 64.29 (C4),
57.60 (C6), 54.16 (C3a), 45.06 (NMe), 36.97 (3a-CH2),
27.98 (C7). Found, %: C 68.63; H 6.46; N 17.89.
C27H30N6O2. Calculated, %: C 68.92; H 6.27; N 17.85.
Mass spectrum: m/z 470. Calculated: M 470.537.
1
1202, 1178, 1158, 1119, 1091, 1063, 1041, 1020. H
NMR spectrum (CDCl3), δ, ppm (J, Hz): 7.98 d (2H,
o-H, J = 7.7), 7.71 s (1H, 4-H), 7.36 t (2H, m-H, J =
7.5), 7.09 t (1H, p-H, J = 7.4), 3.50 t (2H, CH2, J =
b. The mother liquor was combined with the
methanol washings, and 3 mL of 40% aqueous
formaldehyde was added. Extensive separation of
crystals started immediately. After 0.5 h, the crystals
were filtered off and washed with cold methanol to
isolate an additional portion, 4.06 g, of V as white
crystals. The IR spectra of both samples were identical.
13
7.4), 3.17 s (3H, NMe), 2.86 t (2H, CH2, J = 7.4). C
NMR spectrum (CDCl3), δC, ppm: 163.25 (C3), 150.27
(C4), 144.85 (C7a), 139.86 (Ci), 128.59 (Cm), 123.75
(Cp), 118.73 (Co), 101.70 (C3a), 49.13 (C6), 44.04
(NCH3), 22.94 (C7). Found, %: C 68.87; H 5.86; N
18.28. C13H13N3O. Calculated, %: C 68.71; H 5.77; N
18.48.
c. Pyrazolopiperidine IIa, 3.0 g, synthesized from
keto ester Ib and phenylhydrazine in methanol at 15–
20°C [1], was recrystallized was dissolved in 30 mL of
boiling 96% ethanol. The solution was cooled and kept
for two days at room temperature, and the precipitate
was filtered off, washed on a filter with ethanol, and
dried. Yield 1.31 g. According to the TLC data, the
product was identical to samples prepared as described
in a and b.
Transformation of pyrazolopiperidine IIa in
boiling methanol. A solution of 2.3 g ( 0.01 mol) of
pyrazolopiperidine IIa in 20 mL of methanol was
heated for 4 h under reflux, evaporated to a volume of
5 mL, and left overnight. The crystals were filtered off
and washed with cold methanol to isolate 0.6 g of
compound V which was identical to samples obtained
in other ways.
The filtrate and the washings were combined and
mixed with 10 g of silica gel. After a time, silica gel
was separated and dried under reduced pressure at 40–
50°C. The dry powder was placed into a narrow Schott
funnel and slowly washed with 100 mL of methylene
chloride. Removal of the solvent gave 0.6 g of a
3a,3a′-Methylenebis(5-methyl-2-phenyl-3,3a,4,5,6,7-
hexahydro-2H-pyrazolo[4,5-c]pyridin-3-one) dihyd-
rochloride (V)·2HCl. Dry hydrogen chloride was
passed through a solution of V in methylene chloride.
The precipitate was filtered off and recrystallized from
methanol. The product is readily soluble in water and
DMSO. IR spectrum (KBr), ν, cm–1: 3424 v.br, 3106,
3061, 3012, 2943, 2665, 2585, 2544, 2450, 1711,
1630, 1595, 1497, 1462, 1429, 1405, 1359, 1323,
1273, 1236, 1138, 1094, 1065. Found, %: C 59.98; H
1
yellow thick oily substance. According to the H and
13C NMR data, it contained approximately equal
amounts of compounds VIII and IX and a small
impurity of unidentified product.
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TAUTOMERISM OF AZA HETEROCYCLES: V.
1177
3a,5-Dimethyl-2-phenyl-3,3a,4,5,6,7-hexahydro-
2H-pyrazolo[4,3-c]pyridin-3-one (VIII). 1H NMR
spectrum (CDCl3), δ, ppm (J, Hz): 7.92 (2H, o-H),
7.39 (2H, m-H), 7.17 (1H, p-H), 3.13 m (1H, 6-H),
2.96 m (1H, 4-H), 2.73 m and 2.61 m (1H each, 7-H),
2.35 s (3H, NMe), 2.08 m (1H, 6-H), 2.05 m (1H, 4-
methylene chloride, and the upper layer was a light
yellow low-mobile oily substance which slowly
crystallized. The resulting powder was treated with
15 mL of methanol, and about 0.05 g (6%) of light
yellow crystals of VII separated from the solution after
some time. mp 248–249°C; published data [17]: mp
237–239°C (decomp., from 2-methoxyethanol). After
storage for several years, crystals of VII were
transformed into a red tarry material. 1H NMR
spectrum, δ, ppm (J, Hz): in DMSO-d6: 9.49 s (1H,
NH), 7.22 t (2H, m-H, J = 7.3), 7.17 d (2H, o-H, J =
7.3), 6.80 t (1H, p-H, J = 7.3), 3.48 t (2H, 5-H, J =
6.6), 2.86 s (3H, NMe), 2.72 t (2H, 4-H, J = 6.6); in
CDCl3: E isomer: 7.50 s (1H, NH), 7.10 d (2H, o-H,
J = 7.3), 6.95 t (2H, m-H, J = 7.3), 6.88 t (1H, p-H, J =
7.3), 3.54 t (2H, 5-H, J = 6.6), 2.93 s (3H, NMe), 2.68
t (2H, 4-H, J = 6.6); Z isomer: 12.04 s (1H, NH), 7.32–
7.23 m (5H, Ph), 3.59 t (2H, 5-H, J = 6.6), 3.03 s (3H,
NMe), 2.73 t (2H, 4-H, J = 6.6). 13C NMR spectrum
(DMSO-d6), δC, ppm: 164.38 (C2), 145.08 (Ci), 138.41
(C3), 129.02 (Cm), 120.00 (Cp), 113.15 (Co), 44.28 (C5),
30.07 (NMe), 21.82 (C4). IR spectrum (mineral oil), ν,
cm–1: 3278, 1678, 1660 pl, 1625, 1545, 1496, 1312,
1300, 1272. Mass spectrum: m/z 203.
13
H), 1.53 s (3H, 3a-Me). C NMR spectrum (CDCl3),
δC, ppm: 175.44 (C3O), 165.57 (C7), 138.23 (Ci),
128.76 (Cm), 124.84 (Cp), 118.63 (Co), 62.37 (C4),
57.32 (C6), 51.50 (C3a), 45.09 (NMe), 27.39 (C7),
18.56 (3a-Me).
Methyl 3-(2-phenylhydrazinylidene)-4,5-dihydro-
1
3H-pyrrole-2-carboxylate (IX). H NMR spectrum
(CDCl3), δ, ppm (J, Hz): 7.32 (1H, NH), 7.27 (2H, m-
H), 7.12 (2H, o-H), 6.93 (1H, p-H), 4.28 (2H, 5-H),
3.97 (3H, OMe), 2.61 (2H, 4-H). 13C NMR spectrum
(CDCl3), δC, ppm: 163.84 (C2), 162.71 (C=O), 145.66
(C3), 143.70 (Ci), 129.22 (Cm), 121.46 (Cp), 113.61
(Co), 58.02 (C5), 52.57 (OCH3), 25.12 (C4).
The sorbent was then eluted with methylene
chloride–methanol (10 : 1). The solvent was removed
to obtain 0.86 g of a light brown oily substance which
was dissolved in 5 mL of hot acetone. After cooling,
the precipitate was filtered off and recrystallized once
more from acetone. Yield of VI 0.2 g, light brown
crystals whose IR spectrum was identical to that given
above.
ACKNOWLEDGMENTS
The authors thank Prof. Sh.K. Latypov for his
participation in structural studies of the described
compounds by NMR spectroscopy and R.Z. Musin for
recording the mass spectra.
A small amount of gaseous hydrogen chloride was
passed through the mother liquor after separation of
pyrazolotetrahydropyridine VI. After some time, two
kinds of crystals separated and were sorted out from
each other manually. The colorless crystals underwent
recrystallization at 225–230°C and gradually decom-
posed above 300°C. Their structure was determined by
X-ray analysis as hydrochloride hydrate VIII· HCl·H2O
(XIII).
This study was performed under financial support
by the Russian Foundation for Basic Research and by
the Academy of Sciences of Tatarstan Republic
(project no. 12-03-97042r_povolzh’e_a).
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