Regioisomeric 4-amino- and 6-aminopyrazolo[3,4-b]pyridines: Synthesis and structure determination by NMR spectroscopy and X-ray diffraction

Article abstract of DOI:10.1007/s11172-012-0125-3

Abstrac: The methods for selective synthesis of regioisomeric 4-amino- and 6-amino-1-aryl-3-R-1H-pyrazolo[3,4-b]pyridine-5-carbonitriles were developed. Heating 4-amino-substituted pyrazolo[3,4-b]pyridines gave 6-amino-substituted isomers in quantitative yield. Spectral differences characteristic of both isomers were evaluated based on the ¹³C NMR spectra.

Full text of DOI:10.1007/s11172-012-0125-3

Russian Chemical Bulletin, International Edition, Vol. 61, No. 4, pp. 891—896, April, 2012
891
Regioisomeric 4ꢀaminoꢀ and 6ꢀaminopyrazolo[3,4ꢀb]pyridines: synthesis and
structure determination by NMR spectroscopy and Xꢀray diffraction
A. A. Petrov,a A. N. Kasatochkin,a E. E. Emelina,a and M. Haukkab
aDepartment of Chemistry, Saint Petersburg State University,
26 Universitetsky prosp., 198504 Saint Petersburg, Russian Federation.
Fax: +7 (812) 428 6939. Eꢀmail: aap47@hotmail.ru
bDepartment of Chemistry, University of Joensuu,
P. O. Box 111, FIꢀ80100 Joensuu, Finland
The methods for selective synthesis of regioisomeric 4ꢀaminoꢀ and 6ꢀaminoꢀ1ꢀarylꢀ3ꢀRꢀ
1Hꢀpyrazolo[3,4ꢀb]pyridineꢀ5ꢀcarbonitriles were developed. Heating 4ꢀaminoꢀsubstituted pyrꢀ
azolo[3,4ꢀb]pyridines gave 6ꢀaminoꢀsubstituted isomers in quantitative yield. Spectral differꢀ
ences characteristic of both isomers were evaluated based on the 13C NMR spectra.
Key words: aminopyrazoles, pyrazolo[3,4ꢀb]pyridines, regioisomers, ethoxymethylideneꢀ
malononitrile.
5ꢀAminoꢀ1ꢀphenylpyrazoles are the key compounds
for the synthesis of novel substituted pyrazoles and pyrꢀ
azolo[3,4ꢀb]pyridines.1—3 Combining pharmacophoric
pyrazole and pyridine fragments in one molecule opens
access to a series of nitrogenꢀcontaining polycyclic comꢀ
pounds with valuable biological properties. According to
the published data, among pyrazolo[3,4ꢀb]pyridine derivꢀ
atives, compounds exhibiting antiproliferative,4 antituꢀ
mor,5 antimicrobial and antibacterial,6—8 antithrombotic9
as well as antiviral10 activity were found. Therefore, these
compounds inhibit Pim kinases,11 phosphoinositide 3ꢀkiꢀ
nase,12 and acetylcholinesterase.13
Annulation of a pyridine ring to a pyrazole rings (reacꢀ
tion of 1ꢀsubstituted 5ꢀaminopyrazoles with dielectroꢀ
philes)3,14—17 and the Friedlander condensation13,18—20 are
commonly used for the synthesis of these compounds.
Alternative approaches towards heterocycles containing
pyrazolo[3,4ꢀb]pyridine fragment are annulation of the
pyrazole ring to the pyridine ring starting from 2ꢀhaloꢀ
genꢀ3ꢀsubstituted pyridines (3ꢀcyanoꢀ21—23 and 3ꢀacetylꢀ24)
and the reaction of 2ꢀNꢀnitrosoꢀ3ꢀacetylpyridines25 with
hydrazines. Pyrazolo[3,4ꢀb]pyridines were also obtained
by regioselective procedures based on the indole26 and
benzopyrane27 ring opening.
The number of publications devoted to both the synthetic
procedure development and assignment of the regiostrucꢀ
ture of the heterocycles bearing pyrazolo[3,4ꢀb]pyridine
moiety based on NMR spectroscopy are scares.
In continuation of our research on the reactions of
Nꢀsubstituted 5ꢀaminopyrazoles with 1,3ꢀdielectrophyles28,
in the present work with the aim of synthesizing functionꢀ
alized pyrazolopyridines selectively, we studied the regioꢀ
selectivity of the reactions of Nꢀarylꢀsubstituted 5ꢀaminoꢀ
pyrazoles with ethoxymethylidenemalononitrile.
Heating a mixture of Nꢀsubstituted 5ꢀaminopyrazoles
1a—c and ethoxymethylidenemalononitrile (2) in refluxꢀ
ing methanol for ~20 h (Scheme 1) resulted selectively in
Scheme 1
A wide range of biological activity of pyrazolo[3,4ꢀb]ꢀ
pyridines encourages the search for new compounds of
these type and modification of the known synthetic methods.
Cyclocondensation of 5ꢀaminopyrazoles with 1,3ꢀdiꢀ
electrophiles can results in two regioisomeric pyrazolo[3,4ꢀb]ꢀ
pyridines, which differ in the position of the substituents at
the C(4) and C(6). The structure of these compounds is often
difficult to establish even only one regioisomer is formed.
1, 3: Ar = Ph (a), 3ꢀClC6H4 (b), 4ꢀEtO2CC6H4 (c)
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 0886—0991, April, 2012.
1066ꢀ5285/12/6104ꢀ0891 © 2012 Springer Science+Business Media, Inc.

892
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 4, April, 2012
Petrov et al.
4ꢀaminoꢀ1ꢀarylꢀ3ꢀmethylꢀ1Hꢀpyrazolo[3,4ꢀb]pyridineꢀ5ꢀ
carbonitriles 3a—c in the yields of 40—53%.29—31
It was shown by special experiments that heating of
compounds 3 in refluxing butyl alcohol lead to regioisoꢀ
meric compounds 4 in nearly quantitative yields (Scheme 3).
This reaction can also be performed in the inert solvent,
diphenyl ether, at 230—235 C.
The reaction involves initial formation of linear
structures, 2ꢀ(1ꢀarylꢀ3ꢀmethylꢀ1Hꢀ5ꢀpyrazolylaminoꢀ
methylidene)malononitriles of the type A, arising from
the nucleophilic attack of the exocyclic nitrogen atom of
the aminopyrazole on the carbon atom of the ethoxyꢀ
methylidene group of compound 2. The structures of
these compounds were evaluated from the analysis of the
1H NMR spectra of the reaction mixtures. The reaction of
aminopyrazole 1a carried out at 20 C in MeOH for 3 days
afforded intermediate compound A and product 3a in
40 and 60%, respectively. In the 1H NMR spectra, the low
field signals characteristic of the linear structure A were
observed, namely, the doublets of the NH group and the
neighboring =CH moiety at  11.12 and 8.01, respectiveꢀ
ly, with spinꢀspin coupling constant of 9.5 Hz. 2ꢀ[1ꢀ(3ꢀ
Chlorophenyl)ꢀ3ꢀmethylꢀ1Hꢀ5ꢀpyrazolylaminomethylꢀ
idene]malononitrile A was obtained by threeꢀcomponent
reaction of 5ꢀaminopyrazole 1b, malononitrile, and triꢀ
ethyl orthoformate in refluxing methanol.32
Scheme 3
Thus, apparently, upon heating the starting reactants
in refluxing butyl alcohol, initially formed pyrazolopyꢀ
ridines 3a—c (the kinetic control products) isomerize into
thermodynamically more stable compounds 4a—c (see
Scheme 3). This issue was confirmed by the data summaꢀ
rized in Table 1, which indicate selective formation of
regioisomer 3 in the reaction mixture during first 30 min
of the reaction, while the prolonged heating resulted in the
accumulation of regioisomer 4.
At the same time, heating 5ꢀaminopyrazoles 1a—d with
ethoxymethylidenemalononitrile (2) in refluxing butyl
alcohol for ~20 h gave regioisomeric 6ꢀaminoꢀ1ꢀarylꢀ3ꢀ
methylꢀ1Hꢀpyrazolo[3,4ꢀb]pyridineꢀ5ꢀcarbonitriles 4a—d
in 57—65% yields (Scheme 2).
It is possible to assume that isomerization involved
a reaction sequence of pyridine ring opening of compound 3
by cleavage of the C—C bond, prototropic isomeriꢀ
zation, [1,3] shift of the —CH=C(CN)C=NH group,
and the ring closure with new C—N bond formation
(Scheme 4).
Scheme 2
Ratios of the formed regioisomers were determined
1
based on H NMR spectra of the reaction mixtures. The
methyne proton of the pyridine fragment and the protons
of the methyl group of regioisomer 3 resonate in the stronꢀ
Table 1. Ratio of regioisomers 3 and 4 formed at refluxꢀ
ing 5ꢀaminopyrazoles 1 and ethoxymethylidenemalonoꢀ
nitrile (2) in butyl alcohol depending on the reaction
time (t)*
t/min
Ratio of regioisomers
1, 3, 4: R = Me, Ar = Ph (a), 3ꢀClC6H4 (b), 4ꢀEtO2CC6H4 (c);
R = 4ꢀClC6H4, Ar = Ph (d)
3a : 4a
3b : 4b
3c : 4c
30
91 : 9
76 : 24
67 : 33
31 : 69
12 : 88
10 : 90
5.5 : 94.5
94 : 6
50 : 50
31 : 69
11 : 89
6 : 94
93.5 : 6.5
77 : 23
54 : 46
36 : 64
18.5 : 81.5
10 : 90
The similar compounds were previously obtained13,20,33
only by the reactions of 5ꢀaminoꢀ3ꢀRꢀ1ꢀarylꢀ1Hꢀpyrꢀ
azoloꢀ4ꢀcarbaldehydes with malononitrile. In the case of
Nꢀsubstituted 5ꢀaminopyrazole 1e (Ar = Ph, R = But), no
formation of pyrazolo[3,4ꢀb]pyridines 3 or 4 was detected
neither refluxing the starting reactants in butyl alcohol nor
at heating them in diphenyl ether at 230—235 C. The
linear structures A were not also found.
100
160
250
330
400
550
3.5 : 96.5
1.5 : 98.5
3.5 : 96.5
* According to the 1H NMR data of the samples of the
reaction mixture taken upon the reaction.

4ꢀAminoꢀ and 6ꢀaminopyrazolo[3,4ꢀb]pyridines
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 4, April, 2012
893
Scheme 4
ger field as compared with those of isomer 4; in contrary,
the NH2 group resonates in the lower field.
This transformation was also performed in threeꢀcomꢀ
ponent version by refluxing 5ꢀaminopyrazole 1b, malonoꢀ
nitrile, and triethyl orthoformate in butyl alcohol. Comꢀ
pound 4b was the only product of the reaction.
compared with the standard bond lengths (1.54, 1.47, 1.45 Å,
respectively)34 indicating substantial delocalization of the
ꢀ and nꢀelectrons.
In the crystal, molecules form centrosymmetric cyclic
dimers due to interactions of the amino group hydrogens
with the nitrile group nitrogens (N—H...NC—). These
supramolecular associates are further connected into
a threeꢀdimensional framework by weaker contacts
C(12)—H...CN and C(12)—H...C(5) (the shortest disꢀ
tances C...C are 3.308(2) and 3.380(2) Å, respectively).
Besides, the second amino group hydrogen is Hꢀbonded
to the solvate acetonitrile molecule presented in a crystalꢀ
line lattice. The parameters of hydrogen bonds in the comꢀ
pound 4b are given below (D is donor, A is acceptor).
Compositions and structures of the compounds synꢀ
1
thesized were evaluated using H and 13C NMR spectroꢀ
scopy, mass spectrometry (ESI), and Xꢀray diffraction.
Relative orientation of the substituents in the pyridine
ring of pyrazolo[3,4ꢀb]pyridines 3 and 4 (H and NH2) was
established based on the nuclear Overhauser effect obꢀ
served in the 2D NOESY spectrum. In NOESY spectrum
of compound 4a in CDCl3, cross peaks of high intensity
for the couplings of the protons of the methyl group at
 2.56 with the CH(4) at  8.12 indicate their neighboring
location, which can be realized only for regioisomer 4a but
not for alternative structure 3a. These data allowed us
to identify in the 13C NMR spectra the signals of the
carbon atoms C(5), C(3a), C(6), C(4), and CH3 characꢀ
teristic of regioisomeric pyrazolo[3,4ꢀb]pyridines 3a—d
and 4a—d (Table 2).
The structure of compound 4b was confirmed by
a single crystal Xꢀray diffraction. Geometry of the moleꢀ
cule of 4b is shown on Fig. 1. The hydrogen atom is bondꢀ
ed to the C(4) and the amino group is located at the C(6).
Heteroatomic bicyclic system N(1)N(2)C(3)C(3a)C(4)ꢀ
C(5)C(6)N(7)C(7a) is nearly planar, the maximum deviꢀ
ation from the mean plane is 0.019 Å (the C(3) atom).
All formally single bonds of the pyrazolopyridine system
(C—C, C—N, and N—N) are significantly shortened as
D—H...A
d/Å
Angle DHA
/deg
D—H
H...A
D...A
N(4)—H(2N)...N(3) 0.85(2) 2.25(2) 3.079(2) 165.8(19)
N(4)—H(2M)...N(8) 0.87(2) 2.25(2) 3.103(2) 166.8(18)
In summary, varying the reaction conditions, the exꢀ
perimental procedures towards regioisomeric 4ꢀaminoꢀ
and 6ꢀaminoꢀ1ꢀarylꢀ3ꢀRꢀ1Hꢀpyrazolo[3,4ꢀb]pyridinꢀ5ꢀ
carbonitriles were developed. It was shown that 6ꢀaminoꢀ
substituted pyrazolo[3,4ꢀb]pyridines are thermodynamiꢀ
cally more stable than 4ꢀamino derivatives. The characꢀ
teristic spectral differences between regioisomers were deꢀ
termined based on the 13C NMR.
C(33A)
N(2)
C(3)
C(15)
C(16)
N(1)
Table 2. 13C Shifts of characteristic Cꢀatoms of pyrazoꢀ
lo[3,4ꢀb]pyridines 3a—c and 4a—d
C(3A)
C(4)
C(14)
C(11)
C(7A)
C(12)
Atom
C

C(5)
C(13)
C(6)
C(55)
3a—c
4a—c
4d
N(7)
С(5)
C(3a)
C(4)
C(6)
CH3
65.9—67.0
101.1—101.2
116.0—116.3
149.3—149.4
16.2—16.3
87.1—87.4
109.2—109.5
138.3—138.5
158.9
88.9
106.6
139.2
158.6
—
C(18)
Cl(1)
N(3)
C(17)
N(4)
N(8)
11.9—12.0
Fig. 1. Crystal structure of compound 4b.

894
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Petrov et al.
(br.s, 2 H, NH2); 7.35—7.50 (m, 3 H, H arom.); 7.52 (s, 1 H,
H(2´) arom.); 7.90 (s, 1 H, H(6)). 13C NMR (without proton
decoupling, DMSOꢀd6), : 16.16 (q, CH3, J = 128.7 Hz); 66.55
(t, C(5), J = 1.8 Hz); 101.08 (d, C(3a), J = 1.8 Hz); 116.16 (d, C(4),
3J = 13.2 Hz); 117.18 (d, CN, J = 8.0 Hz); 122.90 (ddd, C(6´)
arom., J = 166.2 Hz, 3J = 6.5 Hz, 2J = 1.5 Hz); 124.10 (dt, C(2´)
arom., J = 168.8 Hz, 2J = 5.0 Hz); 127.93 (ddd, C(4´) arom.,
J = 167.8 Hz, 3J = 6.0 Hz, 2J = 1.5 Hz); 131.17 (d, C(5´) arom.,
J = 166.3 Hz); 133.70 (m, C(3´) arom.); 138.15 (dd, C(1´) arom.,
3J = 9.3 Hz, 2J = 2.9 Hz); 148.92 (m, C(3)); 149.38 (d, C(6),
J = 156.1 Hz); 151.47 (d, C(7a), 3J = 5.2 Hz).
Experimental
1
H and 13C NMR spectra were run on a Bruker DPXꢀ300
instrument (300.13 and 75.47 MHz, respectively) at 22 C in
CDCl3, DMSOꢀd6 or DMSOꢀd6—CCl4 (1 : 2). Chemical shifts
are given in the  scale relative to the residual solvent signals
( 7.28,  76.90 (CDCl3);  2.50,  39.50 (DMSOꢀd6)).
H
C
H
C
Elemental composition was determined by high resolution mass
spectrometry on a Bruker Daltonics microTOF instrument
employing electrospray ionization (ESI) and operating in the
positive ion mode. Malononitrile, ethoxymethylidenemalonoꢀ
nitrile, ethyl orthoformate (Alfa Aesar), and the solvents (proꢀ
duced in Russia) were used. The starting aminopyrazoles,
3ꢀmethylꢀ1ꢀphenylꢀ1Hꢀ5ꢀpyrazolamine (1a) (m.p. 111—112 C
(EtOH)), 3ꢀmethylꢀ1ꢀ(3ꢀchlorophenyl)ꢀ1Hꢀ5ꢀpyrazolamine
(1b) (m.p. 138—139 C (EtOH)), ethyl 4ꢀ(5ꢀaminoꢀ3ꢀmethylꢀ
1Hꢀ1ꢀpyrazolyl)benzoate (1c) (m.p. 157—158 C (EtOH)), and
1ꢀphenylꢀ3ꢀ(4ꢀchlorophenyl)ꢀ1Hꢀ5ꢀpyrazolamine (1d) (m.p.
186—187 C (EtOH)), were synthesized according to the known
procedures.35,36
2ꢀ[1ꢀ(3ꢀChlorophenyl)ꢀ3ꢀmethylꢀ1Hꢀ5ꢀpyrazolylaminomeꢀ
thylidene]malononitrile (A). A mixture of 5ꢀaminopyrazole 1b
(1 mmol), malononitrile (1 mmol), and triethyl orthoformate
(0.5 mL) in MeOH (7 mL) was refluxed for 6 h. The solvent was
removed in vacuo, the residue was recrystallized. Yield 48%,
m.p. 207—208 C (EtOH). High resolution MS, found:
m/z 284.0705 [M + H]+. C14H10ClN5. Calculated: 284.0697
[M + H]+. 1H NMR (DMSOꢀd6), : 2.21 (s, 3 H, Me); 6.39,
6.45 (both s, 1 H, =CH, pyrazole); 7.49—7.62 (m, 4 H, H arom.);
8.04, 8.13 (both br.s, 1 H, =CH); 10.89, 11.23 (both br.s, 1 H,
NH). 13C NMR (DMSOꢀd6), : 13.77 (Me); 53.54 (C(2´));
101.29 (C(4)); 113.48, 115.72 (2 CN); 121.97, 123.98, 127.13,
130.95 (4 C, arom.); 133.54 (C(3´) arom.); 139.38, 139.59 (C(1´)
arom., C(5)); 148.99 (C(3)); 160.31 (C(1´)).
Ethyl 4ꢀ(4ꢀaminoꢀ5ꢀcyanoꢀ3ꢀmethylꢀ1Hꢀpyrazolo[3,4ꢀb]ꢀ
pyridinꢀ1ꢀyl)benzoate (3c). Yield 53%, m.p. 213—214 C. High
resolution MS, found: m/z 322.1311 [M + H]+. C17H15N5O2.
1
Calculated: 322.1298 [M + H]+. H NMR (DMSOꢀd6—CCl4),
: 1.41 (t, 3 H, Me, J = 6.9 Hz); 2.39 (s, 3 H, Me); 4.36 (q, 2 H,
CH2, J = 6.9 Hz); 7.16 (s, 2 H, NH2); 7.64 (d, 2 H, H arom.,
J = 8.0 Hz); 7.93 (s, 1 H, H(6)); 8.07 (d, 2 H, H arom.,
J = 8.0 Hz). 13C NMR (DMSOꢀd6), : 14.09 (Me); 16.04 (Me);
60.93 (CH2); 67.00 (C(5)); 101.23 (C(3a)); 115.99 (C(4));
117.01 (CN); 123.44 (C(2´)); 128.52 (C(4´)); 130.39 (C(3´));
140.69 (C(1´)); 149.24, 149.33 (CMe, =CH); 151.29 (C(7a));
164.94 (C=O).
Reaction of 5ꢀaminopyrazoles 1 with ethoxymethylidenemaꢀ
lononitrile (2) in BuOH. A mixture of 5ꢀaminoꢀ1ꢀarylpyrazole 1
(1 mmol) and ethoxymethylidenemalononitrile (2) (1 mmol) in
BuOH (3 mL) was refluxed for 20 h. The solvent was removed
in vacuo, the residue was recrystallized from EtOH.
6ꢀAminoꢀ3ꢀmethylꢀ1ꢀphenylꢀ1Hꢀpyrazolo[3,4ꢀb]pyridineꢀ5ꢀ
carbonitrile (4a). Yield 65%, m.p. 193—194 C (cf. Ref. 33:
m.p. 226 C; cf. Ref. 13: m.p. 223—225 C). High resolution MS,
found: m/z 250.1073 [M + H]+. C14H11N5. Calculated: 250.1087
[M + H]+. 1H NMR (CDCl3), : 2.56 (s, 3 H, CH3); 5.38 (br.s,
2 H, NH2); 7.31 (t, 1 H, H(4´) arom., J = 8.0 Hz); 7.50 (t, 2 H,
H(3´) arom., J = 8.0 Hz); 8.12 (s, 1 H, H(4)); 8.13 (d, 2 H, H(2´)
arom., J = 8.0 Hz). 1H NMR (DMSOꢀd6), : 2.43 (s, 3 H, CH3);
7.22 (br.s, 2 H, NH2); 7.25 (t, 1 H, H(4´) arom., J = 8.0 Hz);
7.47 (t, 2 H, H(3´) arom., J = 8.0 Hz); 8.17 (d, 2 H, H(2´) arom.,
J = 8.0 Hz); 8.49 (s, 1 H, H(4)). 13C NMR (without proton
decoupling, DMSOꢀd6), : 12.01 (q, CH3, J = 128.7 Hz); 87.10
(t, C(5), J = 4.5 Hz); 109.21 (d, C(3a), J = 3.0 Hz); 117.36
(d, CN, J = 5.0 Hz); 119.95 (dt, C(2´) arom., J = 161.5 Hz,
3J = 8.0 Hz); 125.28 (dt, C(4´) arom., J = 163.5 Hz, 3J = 8.0 Hz);
128.93 (dt, C(3´) arom., J = 161.5 Hz, 3J = 8.5 Hz); 138.44
(d, C(4), J = 169.5 Hz); 139.00 (t, C(1) arom., 3J = 8.5 Hz);
Reaction of 5ꢀaminopyrazoles 1 with ethoxymethylideneꢀ
malononitrile (2) in MeOH (general procedure). A mixture of
5ꢀaminoꢀ1ꢀarylpyrazole 1 (1 mmol) and ethoxymethylideneꢀ
malononitrile (2) (1 mmol) in MeOH (3 mL) was refluxed for
20 h. The solvent was removed in vacuo, the residue was recrysꢀ
tallized from EtOH.
4ꢀAminoꢀ3ꢀmethylꢀ1ꢀphenylꢀ1Hꢀpyrazolo[3,4ꢀb]pyridineꢀ5ꢀ
carbonitrile (3a). Yield 0.10 g (40%), m.p. 172—173 C (from
EtOH) (cf. Ref. 31: m.p. 192—194 C). High resolution MS,
found: m/z 250.1038 [M + H]+. C14H11N5. Calculated: 250.1087
[M + H]+. 1H NMR (DMSOꢀd6), : 2.35 (s, 3 H, CH3); 7.17
(br.s, 2 H, NH2); 7.44—7.54 (m, 5 H, CH arom.); 7.97 (s, 1 H,
H(6)). 13C NMR (CDCl3), : 12.56 (CH3); 68.24 (C(5));
101.47 (C(3a)); 115.67 (C(4)); 117.06 (CN); 124.10 (C(2´), C(6´)
arom.); 129.24 (C(4´) arom.); 130.03 (C(3´), C(5´) arom.);
135.88 (C(1´) arom.); 147.15 (C(3)); 150.87 (C(6));
151.54 (C(7a)). 13C NMR (DMSOꢀd6), : 16.27 (CH3); 65.88
(C(5)); 101.16 (C(3a)); 116.34 (C(4)); 117.32 (CN); 124.23
(C(2´), C(6´) arom.); 128.05 (C(4´) arom.); 129.59 (C(3´), C(5´)
arom.); 136.91 (C(1´) arom.); 148.49 (C(3)); 149.37 (C(6));
151.32 (C(7a)).
2
144.18 (qd, C(3), J = 7.0 Hz, 3J = 2.0 Hz); 151.18 (d, C(7a),
3J = 8.0 Hz); 158.87 (d, C(6), 3J = 6.0 Hz).
6ꢀAminoꢀ1ꢀ(3ꢀchlorophenyl)ꢀ3ꢀmethylꢀ1Hꢀpyrazolo[3,4ꢀb]ꢀ
pyridineꢀ5ꢀcarbonitrile (4b). Yield 0.16 g (57%), m.p. 190—191 C
(from EtOH). High resolution MS, found: m/z 284.0688 [M + H]+.
C14H10ClN5. Calculated: 284.0697 [M + H]+. 1H NMR
(DMSOꢀd6—CCl4 (1 : 2)), : 2.47 (s, 3 H, CH3); 7.01 (br.s, 2 H,
NH2); 7.18 (d, 1 H, H(4´) arom., J = 8.0 Hz); 7.44 (t, 1 H, H(5´)
arom., J = 8.0 Hz); 8.27 (d, 1 H, H(6´) arom., J = 8.0 Hz); 8.30
(s, 1 H, H(2´) arom.); 8.36 (s, 1 H, H(4)). 13C NMR (without
proton decoupling, DMSOꢀd6), : 11.98 (q, CH3, J = 128.6 Hz);
87.35 (t, C(5), 2J = 4.5 Hz); 109.32 (d, C(3a), 2J = 3.0 Hz);
117.19 (d, CN, 3J = 6.0 Hz); 117.73 (dt, C(6´) arom., J = 167.0 Hz,
3J = 5.5 Hz); 118.83 (dm, C(2´) arom., J = 169.5 Hz,
3J = 5.0 Hz); 124.72 (ddd, C(4´) arom., J = 169.0 Hz); 130.55
(d, C(5´) arom., J = 164.6 Hz); 133.38 (m, C(3´) arom.); 138.49
4ꢀAminoꢀ1ꢀ(3ꢀchlorophenyl)ꢀ3ꢀmethylꢀ1Hꢀpyrazolo[3,4ꢀb]ꢀ
pyridineꢀ5ꢀcarbonitrile (3b). Yield 0.11 g (40%), m.p. 202—203 C
(from EtOH). High resolution MS, found: m/z 284.0648
[M + H]+. C14H10ClN5. Calculated: 284.0697 [M + H]+.
1H NMR (DMSOꢀd6—CCl4 (1 : 2)), : 2.37 (s, 3 H, CH3); 7.12

4ꢀAminoꢀ and 6ꢀaminopyrazolo[3,4ꢀb]pyridines
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 4, April, 2012
895
(d, C(4), J = 169.5 Hz); 140.15 (br.d, C(1´) arom., 3J = 10.5 Hz);
144.84 (dq, C(3), 2J = 7.0 Hz, 3J = 2.5 Hz); 151.39 (d, C(7a),
3J = 7.5 Hz); 158.95 (d, C(6), 3J = 6.5 Hz).
Table 4. The principal bond distances (d) and bond angles () in
compound 4b
Ethyl 4ꢀ(6ꢀaminoꢀ5ꢀcyanoꢀ3ꢀmethylꢀ1Hꢀpyrazolo[3,4ꢀb]ꢀ
pyridinꢀ1ꢀyl)benzoate (4c). Yield 62%, m.p. 216—217 C (from
EtOH). High resolution MS, found: m/z 322.1272 [M + H]+.
C17H15N5O2. Calculated: M = 322.1299 [M + H]+. 1H NMR
(DMSOꢀd6—CCl4 (1 : 2)), : 1.41 (t, 3 H, Me, J = 7.0 Hz); 2.48
(s, 3 H, Me); 4.34 (q, 2 H, CH2, J = 7.0 Hz); 7.05 (s, 2 H, NH2);
8.03 (d, 2 H, H arom., J = 8.7 Hz); 8.39 (s, 1 H, H(4)); 8.44 (d, 2 H,
H arom., J = 8.7 Hz). 13C NMR (DMSOꢀd6), : 11.92 (Me);
14.11 (Me); 60.56 (CH2); 87.39 (C(5)); 109.50 (C(3a)); 117.06
(CN); 118.55 (C(2´) arom.); 125.68 (C(4´) arom.); 129.93 (C(3´)
arom.); 138.34 (C(4)); 142.56 (C(1´) arom.); 145.25 (C(3));
151.62 (C(7a)); 158.90 (C(6)); 165.12 (C=O).
Bond
d/Å
Angle
/deg
N(1)—C(7a) 1.3753(19)
N(1)—N(2)
N(2)—C(3)
C(7a)—N(1)—N(2) 110.50(12)
N(7)—C(7a)—N(1) 126.52(14)
N(2)—N(1)—C(11) 118.87(12)
C(3)—N(2)—N(1) 106.62(12)
C(7a)—N(7)—C(6) 114.78(13)
N(2)—C(3)—C(3a) 111.08(14)
C(4)—C(3a)—C(7a) 117.67(14)
C(4)—C(3a)—C(3) 136.64(15)
C(7a)—C(3a)—C(3) 105.66(14)
C(5)—C(4)—C(3a) 116.93(14)
1.3961(18)
1.310(2)
N(7)—C(7a) 1.332(2)
N(7)—C(6)
С(3)—C(3a)
С(3a)—C(4)
С(4)—C(5)
С(5)—C(6)
С(3a)—C(7a) 1.404(2)
N(4)—C(6) 1.345(2)
N(1)—C(11) 1.413(2)
1.341(2)
1.423(2)
1.391(2)
1.382(2)
1.434(2)
C(4)—C(5)—C(6)
N(7)—C(6)—C(5)
120.80(14)
122.48(14)
6ꢀAminoꢀ3ꢀ(4ꢀchlorophenyl)ꢀ1ꢀphenylꢀ1Hꢀpyrazolo[3,4ꢀb]ꢀ
pyridineꢀ5ꢀcarbonitrile (4d). Yield 80%, m.p. 257—258 C (from
BuOH). High resolution MS, found: m/z 346.0776 [M + H]+.
C19H12ClN5. Calculated: 346.0854 [M + H]+. 1H NMR
(DMSOꢀd6—CCl4 (1 : 2)), : 7.05 (br.s, 2 H, NH2); 7.28
(t, 1 H, H(4´) arom., J = 7.3 Hz); 7.48 (d, 2 H, H arom.,
J = 8.7 Hz); 7.50 (t, 2 H, H(3´) arom., J = 7.3 Hz); 8.04 (d, 2 H,
H arom., J = 8.7 Hz); 8.29 (d, 2 H, H(2´) arom., J = 7.3 Hz);
8.75 (s, 1 H, H(4)). 13C NMR (without proton decoupling,
DMSOꢀd6), : 88.88 (t, C(5), 2J = 4.2 Hz); 106.57 (s, C(3a));
117.09 (d, CN, 3J = 6.0 Hz); 120.83 (dm, =CH arom., J = 162.6
Hz); 126.02 (dt, =CH arom., J = 162.6 Hz, 3J = 8.0 Hz); 128.60
(dt, CH arom., J = 163.5 Hz, 3J = 7.0 Hz); 128.92 (dd, CH
arom., J = 161.5 Hz, 3J = 7.5 Hz); 129.97 (dd, CH arom.,
J = 167.5 Hz, 3J = 5.0 Hz); 130.27 (t, C(1´), J = 8.0 Hz); 133.70
(m, C(3)); 151.18 (d, C(7a), 3J = 8.0 Hz); 158.61 (d, C(6),
3J = 6.5 Hz).
Threeꢀcomponent reaction of aminopyrazole 1b, malononitrile,
and ethyl orthoformate. A mixture of aminopyrazole 1b (1 mmol),
malononitrile (1 mmol), and ethyl orthoformate (0.5 mL) in
butyl alcohol was refluxed for 18 h. The solvent was removed
in vacuo, the residue was recrystallized from BuOH. 6ꢀAminoꢀ
1ꢀ(3ꢀchlorophenyl)ꢀ3ꢀmethylꢀ1Hꢀpyrazolo[3,4ꢀb]pyridineꢀ5ꢀ
carbonitrile (4b) was obtained in the yield of 50%.
Isomerization of regioisomers 3 into regioisomers 4. General
procedure A. A mixture of compounds 3a—c (1 mmol) and diꢀ
phenyl ether (1.5 g) was heated at 230—235 C for 0.5 h. The
reaction mixture was diluted with hexane (6 mL), the precipitate
formed was filtered off. Compounds 4a—c were obtained in the
yields of 100% (according to the 1H NMR spectral data).
General procedure B. A mixture of compounds 3a—c
(1 mmol) in BuOH (3 mL) was refluxed for 10 h. The reaction
mixture was cooled to ambient temperature, the solvent was
removed in vacuo. Compounds 4a—c were obtained in the yields
of 100% (according to the 1H NMR spectral data).
Xꢀray diffraction analysis. Single crystal of compound 4b was
obtained by slow concentration of a solution in MeCN at 20 C.
For the Xꢀray diffraction, the crystal was immersed in cryoꢀoil
and mounted on a Nylon loop. The Xꢀray diffraction data were
collected on a Bruker AXS Smart ApexII diffractometer at 100(2) K
(monochromator, MoꢀK radiation ( = 0.71073 Å)). The cell
parameters were refined by APEX2 program.37 The structure
was solved by the direct method using SHELXSꢀ97 software38
and WinGX graphical interface.39 Absorption correction were
applied using SADABS v.2.10 program40. The hydrogen atoms
of the amine group were located in difference Fourier maps and
refined isotropically. The positions of the remained hydrogen
atoms were calculated and refined using the riding model. The
crystal of compound 4b contains the acetonitrile solvation moleꢀ
cule. The crystal structure parameters and experimental details
are given in Table 3, selected bond lengths and angles are listed
in Table 4. The atomic coordinates and displacement parameters
for compound 4b were deposited with the Cambridge Crystalloꢀ
graphyc Data Center (http://ccdc.cam.ac.uk; CCDC 817502).
3
2
(tt, C(4´) arom., J = 11.0 Hz, J = 3.0 Hz); 138.68 (td, C(1´),
3J = 9.5 Hz, 2J = 2.5 Hz); 139.18 (d, C(4), J = 169.6 Hz); 143.33
Table 3. Principal crystallographic data and parameters of
the Xꢀray diffraction experiment for compound 4b
Parameter
Value
Molecular formula
Molecular weight
C16H13ClN6
324.77
T/K
100(2)
Crystal system
Space group
Monoclinic
P21/n
a/Å
b/Å
c/Å
/deg
9.9578(3)
7.4681(2)
20.3407(6)
90
/deg
90.237(2)
90
1512.64(8)
4
1.426
0.261
/deg
V/Å3
Z
dcalc/mg m–3
/mm–1
Crystal size/mm
0.22×0.09×0.08
2.00—26.00
9012
Scanning range/deg
Number of measured reflections
Number of independent reflections
2973
(Rint = 0.0244)
0.0335
R1(I > 2)
This work was financially supported by the Russian Founꢀ
dation for Basic Research (Project No. 10ꢀ03ꢀ00600a).
wR2(I > 2)
0.0819

896
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 4, April, 2012
Petrov et al.
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Received March 28, 2011;
in revised form September 23, 2011