The use of 3-amino-4,6-dimethylpyrazolo[3,4-b]pyridine in the synthesis of novel heterocycles of pharmaceutical interest

Article abstract of DOI:10.1007/s10593-008-0103-8

3-Amino-4,6-dimethylpyrazolo[3,4-b]pyridine was used for the preparation of some novel heterocycles of pharmaceutical interest. The starting material reacted with 2-cyano-3,3-bis(methylthio)acrylate, chloroacetyl chloride, phenyl isothiocyanate, carbon disul-fide, and aromatic aldehydes to give the novel heterocycles. The structures of the hitherto unknown ring systems have been confirmed by analytical and spectral methods.

Full text of DOI:10.1007/s10593-008-0103-8

Chemistry of Heterocyclic Compounds, Vol. 44, No. 6, 2008
THE USE OF 3-AMINO-4,6-DIMETHYL-
PYRAZOLO[3,4-b]PYRIDINE IN THE
SYNTHESIS OF NOVEL HETEROCYCLES
OF PHARMACEUTICAL INTEREST
M. A. Metwally, H. A. Etman, H. E. Gafer, and A. M. Khalil
3-Amino-4,6-dimethylpyrazolo[3,4-b]pyridine was used for the preparation of some novel heterocycles
of pharmaceutical interest. The starting material reacted with 2-cyano- 3,3-bis(methylthio)acrylate,
chloroacetyl chloride, phenyl isothiocyanate, carbon disul- fide, and aromatic aldehydes to give the
novel heterocycles. The structures of the hitherto unknown ring systems have been confirmed by
analytical and spectral methods.
Keywords: pyrazolo[4,3-e]pyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidines, pyrido[2', 3':3,4]pyrazolo-
[1,5-a]pyrimidines, substituted[3,4-b]pyridines.
In general, pyrazolopyridines represent a chemically unique class of non-sedative anxiolytic agents [1].
The treatment of 3-amino-4,6-dimethyl-pyrazolo[3,4-b]pyridine (1) with ethyl 2-cyano-3,3-bis(methylthio)-
acrylate (2) [2] in DMF allowed the isolation of a compound which possessed elemental analysis and spectral
data concordant with the formation of pyridopyrazolopyrimidine 3 (Scheme 1). The IR spectrum is characterized
by the presence of strong absorption bands of NH2 group at ν 3384 and 3247 cm–1 and carbonyl group at ν 1680
1
cm–1. The H NMR spectrum showed a triplet signal at δ 1.50 (CH3 ester), a singlet at δ 2.70 (CH3 pyridine), a
singlet at δ 2.85 (CH3 pyridine), a singlet at δ 3.10 (SCH3), a quartet at δ 4.50 (ester CH2), and a singlet at δ 7.00
(pyridine C-5 proton). The mass spectrum exhibited the molecular ion peak at m/z 332 [M+ + H] (100%)
corresponding to the formula [C15H17N5O2S + H] in addition to other peaks at 189 (54%) and 163 (95%).
Scheme 1
NH2
NH2 O
COOEt
SMe
Me
N
NH
NH
NH2
Me
N
Me
H2O
Me
NH2NH2·
NC
COOEt
SMe
N
N
N
N
N
+
NH
MeS
N
Me
N
Me
N
1
2
4
3
__________________________________________________________________________________________
Department of Chemistry, Faculty of Science, University of Mansoura, P.O. Box 23, Mansoura, Egypt;
e-mail: mamegs@mans.edu.eg. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 891-898,
June, 2008. Original article submitted May 31, 2007, in revised form March 10, 2008.
0009-3122/08/4406-0715©2008 Springer Science+Business Media, Inc.
715

The treatment of compound 3 with hydrazine hydrate afforded the corresponding fused tetracyclic
compound 4. The formation of compound 4 is assumed to proceed via replacement of the SMe group by
hydrazine followed by a loss of 1 mol of ethanol through the reaction with the ester group. The structure of
compound 4 was confirmed by its spectral data and elemental analysis. The IR spectrum of compound 4 showed
three absorption bands at 3422, 3365, and 3211 cm–1 assigned to the stretching vibrations of NH2 and NH
1
groups, in addition to the absorption band at 1654 cm–1 due to the amidic carbonyl group. The H NMR
spectrum revealed three singlet signals at δ 2.80, 2.90, and 7.10 due to the protons of two methyl groups and
pyridine ring, respectively.
Scheme 2
Me
NHCOCH2Cl
ClCH2COCl
1
N
Me
N
N
H
5
PhNCS
O
Me
S
Me
NHCSNHPh
ClCH2COOEt
N
NPh
N
N
N
Me
N
Me
N
N
H
H
6
7
The reaction of compound 1 with chloroacetyl chloride in DMF containing a few drops of triethylamine
afforded the corresponding 3-(N-chloroacetyl- amino)pyrazolo[3,4-b]pyridine derivative 5 (Scheme 2). The IR
spectrum of compound 5 showed three absorption bands at 3247, 3215, and 1669 cm–1 assigned to the stretching
1
vibration of the two NH and CO groups, respectively. The H NMR spectrum revealed two singlet signals at δ
2.40 and 2.50 ppm corresponding to the protons of two methyl groups, a singlet at δ 4.25 due to methylene
protons, a singlet at δ 6.80 for the pyridine H-5 proton, in addition two singlet signals at δ 10.30 and 13.10 ppm
due to the protons of two NH groups. The mass spectrum exhibited the molecular ion peak at m/z 238 [M+]
(95%) in addition to other peaks at 203 (16), 189 (40), 162 (100), 133 (20), 107 (22), 77 (18). The fragmentation
pattern is shown in Scheme (3).
Scheme 3
.
Me
.
Me
N
+
+
H
H
N
N
CH2
–Cl
Cl
O
N
O
N
Me
N
N
N
Me
H
H
5
m/z
203
m/z 238
–CH2
.
+
.
+
Me
N
Me
.
+
H
N
NH2
NH2
– 2Me
–CO
Me
N
O
N
N
N
N
N
N
N
Me
H
H
H
132
m/z
m/z
162
189
m/z
716

When compound 1 was allowed to react with phenyl isothiocyanate in boiling pyridine, the
corresponding thiourea derivative 6 was produced, which underwent cyclization to thiazolidinone derivative 7
by reacting with ethyl chloroacetate in ethanol−pyridine mixture, 3:1. The structure of products 6 and 7 was
secured by their elemental analyses and spectral data. For example, the IR spectrum of compound 7 showed the
characteristic absorption bands of NH (3174) and CO (1720 cm–1). The 1H NMR displayed three singlet signals
at δ 2.50, 2.80, and 4.25 corresponding to the protons of two Me and CH2 groups, a singlet at δ 7.10 for pyridine
H-5 proton, and a multiplet at δ 7.30–7.60 ppm for aromatic protons.
Moreover, the mass spectrum of compound 7 gave m/z 337 [M+] (Irel 100%) which corresponds to the
molecular weight of the molecular formula C17H15N5OS of the assigned structure.
The mass spectrum of compound 6 gave m/z 297 [M+] (Irel 10%) corresponding to the molecular weight
of the molecular formula C15H15N5S of the assigned structure (Scheme 4).
Scheme 4
.
+
Me
H
H
N
N
Ph
S
N
N
N
H
Me
6
m/z 297
–PhNCS
–PhNH2
.
.
+
+
Me
Me
N
NCS
NH2
N
N
N
N
N
Me
Me
H
H
m/z 204
m/z 162
Methyl dithiocarbamates are useful precursors in the synthesis of many important heterocyclic
compounds, e.g., tetrahydroquinazolines or 3,1-benzoxazines [3]. It was found that the base-promoted
nucleophilic addition of compound 1 to carbon disulfide in DMF containing potassium hydroxide afforded the
corresponding non-isolable intermediate potassium salt 8. Subsequent treatment of the latter with methyl iodide
furnished the corresponding methyl-N-(pyrazolo[3,4-b]-3-pyridyl) dithiocarbamate 9 (Scheme 5). The IR
Scheme 5
Me
S
Me
N
S
C
H
Ar
ArCHO
N
Me
N
NHC
NHC
CS2
SMe
MeI
SK
N
1
Me
N
N
N
KOH/DMF
N
H
Me
N
H
Me
N
H
10 a–c
9
8
10 a Ar = 2-O2NC6H4, b Ar = 3-O2NC6H4, c Ar = 4-O2NC6H4
717

spectrum of compound 9 showed absorption bands at 3391 (NH), 3160 (NH), and 1618 cm–1 (C=N). The
1H NMR spectrum revealed two singlet signals at δ 2.40 and 2.60 due to six protons of methyl groups, a singlet
at δ 6.80 for the pyridine proton, in addition to two singlet signals at δ 11.40, and 13.15 due to two NH protons.
The mass spectrum gave the molecular ion peak at m/z 252 [M+] (10%) and other fragmentation peaks at 204
(100), 170 (12), 84 (22), 78 (38).
Azomethines are important building blocks in enantioselective oxidations (chiral oxaziridines) [4],
cycloadditions [5–8], and cyclizations [9]. Compound 1 undergoes condensation with 2-, 3-, and/or 4-nitro-
benzaldehyde in refluxing ethanol containing a few drops of piperidine to give the corresponding Schiff’s
bases 10.
The key starting material, 3-aminopyrazolo[3,4-b]pyridine 1, can react with sodium nitrite to give
pyrazolopyridinyldiazonium salt 11 (Scheme 6).
Scheme 6
Me
OH
–
NCl
+
NaNO2
HCl
N
1
+
N
N
N
H
Me
11
O
OH
Me
Me
N
H
N
N
N
N
N
N
N
N
H
N
H
Me
Me
12
12'
Azo coupling of the pyrazolopyridinyl diazonium salt 11 with phenol in the presence of sodium
hydroxide afforded the corresponding azo derivative 12. The chemical structure of compound 12 was proved by
both analytical and spectral data. The IR spectrum showed stretching frequencies of NH at 3167 and C=N group
1
at 1614 cm–1. The H NMR spectrum in CF3COOD as a solvent revealed two singlet signals at δ 3.00 and 3.20
assigned to the two methyl groups, a singlet at δ 7.50 for pyridine H-5 proton, and two doublet signals at δ 7.70
and 8.20 ppm for the aromatic protons.
According to the previous DFT calculations at the B3LYP/6-31G* level [10], the azo tautomer 12 was
found to be more stable by 3.6 kcal⋅mol–1 than the hydrazono tautomer 12'.
Azo coupling of the pyrazolopyridinyldiazonium salt 11 with 8-hydroxy- quinoline afforded the
corresponding azo derivative 13 (Scheme 7). The chemical structure of compound 13 was established on the
basis of its analytical and spectral data.
Scheme 7
OH
N
O
OH
Me
N
Me
N
H
N
N
N
N
N
N
11
+
N
N
N
H
Me
N
H
Me
13
13'
718

The IR spectrum showed stretching frequencies of NH at 3188, and C=N group at 1616 cm–1. The
1H NMR spectrum in CF3COOD as a solvent revealed two singlet signals at δ 3.00 and 3.15 assigned to the two
methyl groups, a singlet at δ 7.20 for pyridine H-5 proton, and a multiplet signal at δ 7.40-8.20 ppm for the
aromatic protons.
EXPERIMENTAL
IR spectra were recorded on a SP-2000 Pye-Unicam Spectrometer. NMR spectra were obtained with
1
13
Varian-Gemini 200 (200 MHz for 1H) and Brucker 250 (250 MHz for H and 62.5 MHz for C) relative to TMS
as an internal standard, δ 0 ppm. Mass spectra were recorded on a GCMS QP1000EX Schimadzu mass
spectrometer at 70 eV. Melting points (uncorrected) were taken on a Fisher electric melting point apparatus.
Elemental analyses were carried out in the Microanalytical Units, Faculties of Science, Mansoura and Cairo
Universities.
Ethyl 2-amino-8,10-dimethyl-4-methylthiopyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidine-3-carboxy-
late (3). A mixture of compound 1 (0.81 g, 0.005 mol) and ethyl 2-cyano-3,3-bis(methylthio)acrylate (2) (1.08
g, 0.005 mol) in 20 ml DMF was refluxed for 4 h, and then allowed to cool. The solid product that precipitated
on cooling was filtered off, dried, and recrystallized from DMF as brown crystals. Yield 77%; mp 286–287°C.
1
IR spectrum, ν, cm–1: 3384, 3247 (NH2), and 1680 (CO). H NMR spectrum (CDCl3/CF3COOD), δ, ppm (J,
Hz): 1.50 (3H, t, J = 7, CH3); 2.70 (3H, s, CH3); 2.85 (3H, s, CH3); 3.10 (3H, s, CH3); 4.50 (2H, q, J = 7, CH2);
7.00 (1H, s, H-5 pyridine). Mass spectrum (M+H; CI iso-butane), m/z (Irel,%): 332 (100), 189 (54), 163 (95).
Found, %: C 54.22; H 5.14; N 21.05. C15H17N5O2S (331.39). Calculated, %: C 54.36; H 5.17; N 21.13.
4-Amino-6,8-dimethyl-1,2-dihydro-3H-pyrazolo[4,3-e]pyrido[2',3':3,4]pyrazolo-[1,5-a]pyrimidin-
3-one (4). A mixture of compound 3 (1.65 g, 0.005 mol) and hydrazine hydrate (0.50 ml, 0.01 mol) in 20 ml
DMF was refluxed for 4 h, and then allowed to cool. The reaction mixture was poured into ice-cooled water, and
the precipitate was filtered off, dried, and recrystallized from ethanol−DMF mixture (1:1) as red crystals. Yield
1
44%; mp 265–266°C. IR spectrum, ν, cm–1: 3422, 3365, 3211 (NH2, NH), and 1654 (CO). H NMR spectrum
(CDCl3/CF3COOD), δ, ppm: 2.80 (3H, s, CH3); 2.90 (3H, s, CH3); 7.10 (1H, s, H-5 pyridine). Found, %:
C 53.43; H 4.18; N 36.37. C12H11N7O (269.26). Calculated, %: C 53.53; H 4.12; N 36.41.
2-Chloro-N-(4,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (5). To a solution of compound
1 (0.81 g, 0.005 mol) in DMF (15 ml) containing anhydrous sodium carbonate (0.70 g), chloroacetyl chloride
(0.8 ml, 0.01 mol) was added dropwise with stirring at room temperature. Stirring was continued for 4 h, and the
reaction mixture was poured into ice-cooled water. The precipitate was collected by filtration, dried, and
recrystallized from ethanol−DMF mixture (1:1). Yield 84%; mp > 300°C. IR spectrum, ν, cm–1: 3247, 3215
1
(NH), and 1669 (CO). H NMR spectrum (DMSO), δ, ppm: 2.40 (3H, s, CH3); 2.50 (3H, s, CH3); 4.25 (2H, s,
13
CH2); 6.80 (1H, s, H-5 pyridine); 10.30 (1H, s, NH); 13.10 (1H, s, NH). C NMR spectrum (DMSO), δ, ppm:
15.96; 22.50; 40.76; 106.98; 116.47; 135.36; 139.99; 150.64; 156.59; 165.35. Mass spectrum (EI), m/z (Irel,%):
238 (95), 203 (16), 189 (40), 162 (100), 133 (20), 107 (22), 77 (18). Found, %: C 50.40; H 4.60; N 23.52.
C10H11ClN4O (238.67). Calculated, %: C 50.32; H 4.65; N 23.47.
1-(4,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-3-phenylthiourea (6). A mixture of compound 1
(1.62 g, 0.01 mol) and phenyl isothiocyanate (1.20 ml, 0.01 mol) in pyridine was refluxed for 5 h and then
allowed to cool. The solid product 6 was collected and recrystallized from DMF as white crystals. Yield 75%;
mp > 300°C. IR spectrum, ν, cm–1: 3436, 3208, 3168 (NH), and 1641 (C=N). 1H NMR spectrum
(CDCl3/CF3COOD), δ, ppm: 2.80 (3H, s, CH3); 2.90 (3H, s, CH3); 7.10 (1H, s, H-5 pyridine); 7.20-7.50 (5H, m,
Ar-H). Mass spectrum (EI), m/z (Irel,%): 297 (10), 263 (18), 204 (100), 162 (95), 135 (15), 93 (30), 78 (68), 63
(68). Found, %: C 60.63; H 5.26; N 23.45. C15H15N5S (297.38). Calculated, %: C 60.58; H 5.08; N 23.55.
719

3-(4,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-(phenylimino)thiazolidin-4-one (7). A mixture
of compound 6 (1.48 g, 0.005 mol) and ethyl chloroacetate (0.55 ml, 0.005 mol) in ethanol−pyridine mixture
(10:10, ml) was refluxed for 4 h, and then allowed to cool. The solid product 7 was collected and recrystallized
from dioxane as yellow crystals. Yield 68%; mp > 300°C. IR spectrum, ν, cm–1: 3174 (NH) and 1720 (CO). 1H
NMR spectrum (CDCl3/CF3COOD), δ, ppm: 2.50 (3H, s, CH3); 2.80 (3H, s, CH3); 4.25 (3H, s, CH3); 7.10 (1H,
s, H-5 pyridine); 7.30–7.60 (5H, m, Ar-H). Mass spectrum (EI), m/z (Irel,%): 337 (100), 290 (30), 264 (52), 189
(16), 160 (32), 149 (30), 104 (40), 77 (37). Found, %: C 60.48; H 4.56; N 20.67. C17H15N5OS (337.40).
Calculated, %: C 60.52; H 4.48; N 20.76.
Methyl N-(pyrazolo[3,4-b]pyridin-3-yl)dithiocarbamate (9). To a well stirred solution of compound 1
(1.62 g, 0.01mol) in DMF (20 ml) in an ice-bath were added dropwise and successively aqueous potassium
hydroxide (0.56 g in 5 ml H2O), carbon disulfide (0.6 ml), and methyl iodide (0.65 ml). Stirring was continued
for 3 h, and the mixture was then poured into water. The solid thus obtained was filtered off, washed with water,
and recrystallized from ethanol. Yield 62%; mp 246-247°C. IR spectrum, ν, cm–1: 3391, 3160 (NH), and 1618
(C=N). 1H NMR spectrum (DMSO), δ, ppm: 2.40 (3H, s, CH3); 2.60 (6H, s, 2CH3); 6.80 (1H, s, H-5 pyridine),
11.40 (1H, s, NH); 13.15 (1H, s, NH). Mass spectrum (EI), m/z (Irel,%): 252 (10), 204 (100), 170 (12), 84 (22),
78 (38). Found, %: C 47.40; H 4.85; N 22.13. C10H12N4S2 (252.36). Calculated, %: C 47.59; H 4.79; N 22.20.
N-(Nitrobenzylidene)-1H-pyrazolo[3,4-b]-pyridin-3-amines (10) (General procedure). A mixture of
compound 1 (0.81 g, 0.005 mol) and nitrobenzaldehyde (0.75 g, 0.005 mol) in ethanol containing of piperidine
(0.5 ml) was refluxed for 2 h. The solid product precipitated on cooling was filtered off and recrystallized from
ethanol.
N-(2-Nitrobenzylidene)-4,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-3-amine (10a). Yield 80%; mp
246-247°C. IR spectrum, ν, cm–1: 3096 (NH) and 1603 (C=N). 1H NMR spectrum (CDCl3/CF3COOD), δ, ppm:
2.90 (3H, s, CH3); 3.00 (3H, s, CH3); 7.30 (1H, s, H-5 pyridine); 7.60–8.20 (4H, m, Ar-H); 10.00 (1H, s,
N=CH). Mass spectrum (EI), m/z (Irel,%): 295 (18), 249 (15), 162 (31), 133 (15), 77 (16), 40 (100). Found, %:
C 61.13; H 4.60; N 23.65. C15H13N5O2 (295.30). Calculated, %: C 61.01; H 4.44; N 23.72.
N-(3-Nitrobenzylidene)-4,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-3-amine (10b). Yield 84%; mp
231-242°C. IR spectrum, ν, cm–1: 3093 (NH) and 1608 (C=N). 1H NMR spectrum (CDCl3/CF3COOD), δ, ppm:
2.90 (3H, s, CH3); 3.00 (3H, s, CH3); 7.30 (1H, s, H-5 pyridine); 7.70–8.55 (3H, m, Ar-H); 8.80 (1H, m, Ar-H);
10.00 (1H, s, N=CH). Mass spectrum (EI), m/z (Irel,%): 295 (100), 249 (40), 173 (44), 147 (45). Found, %:
C 61.16; H 4.33; N 23.81. C15H13N5O2 (295.30). Calculated, %: C 61.01; H 4.44; N 23.72.
N-(4-Nitrobenzylidene)-4,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-3-amine (10c). Yield 84%;
mp >300°C. IR spectrum, ν, cm–1: 3089 (NH) and 1597 (C=N). 1H NMR spectrum (CDCl3/CF3COOD), δ, ppm
(J, Hz): 2.90 (3H, s, CH3), 3.00 (3H, s, CH3); 7.30 (1H, s, H-5 pyridine); 8.25 (2H, d, J = 8, Ar-H); 8.50 (2H, d,
J = 8, Ar-H); 10.10 (1H, s, N=CH). Mass spectrum (EI), m/z (Irel,%): 295 (100), 249 (48), 162 (30), 173 (12),
147 (40), 51 (18). Found, %: C 61.12; H 4.46; N 23.80. C15H13N5O2 (295.30). Calculated, %: C 61.01; H 4.44;
N 23.72.
Synthesis of dyes 12 and 13 (General Method). The solution of diazonium salt 11 (0.01 mol) was
added with continuous stirring to a cold solution (0-5ºC) of phenol (0.01 mol) or 8-hydroxyquinoline in 10%
sodium hydroxide (25 ml). The reaction mixture was stirred at 0-5ºC for 2 h, and then neutralized with diluted
HCl. The solid product was collected by filtration, dried, and recrystallized from ethanol-DMF mixture (3:1).
4-(4,6-Dimethylpyrazolo[3,4-b]pyridin-3-ylazo)phenol (12). Yield 82%; mp 267-268°C. IR spectrum,
1
ν, cm–1: 3167 (NH) and 1614 (C=N). H NMR spectrum (CF3COOD), δ, ppm (J, Hz): 3.00 (3H, s, CH3); 3.20
(3H, s, CH3); 7.50 (1H, s, H-5 pyridine); 7.70 (2H, d, J = 8, Ar-H); 8.20 (1H, d, J = 8, Ar-H). Found, %:
C 62.78; H 4.81; N 26.13. C14H13N5O (267.29). Calculated, %: C 62.91; H 4.90; N 26.20.
5-(4,6-Dimethylpyrazolo[3,4-b]pyridin-3-ylazo)-8-hydroxyquinoline (13). Yield 88%; mp > 300°C.
IR spectrum, ν, cm–1: 3188 (NH) and 1616 (C=N). 1H NMR spectrum (CF3COOD), δ, ppm: 3.00 (3H, s, CH3);
720

3.15 (3H, s, CH3); 7.20 (1H, s, H-5 pyridine); 7.40–8.20 (5H, m, Ar-H). Found, %: C 64.33; H 4.52; N 26.48.
C17H14N6O (318.33). Calculated, %: C 64.14; H 4.43; N 26.40.
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