Synthesis and structure of 3,4-dihydropyrido[2',3':3,4]pyrazolo[1,5-a][1,3, 5]triazin-2-amines [1]

Article abstract of DOI:10.1002/jhet.851

A new convenient synthon for heterocyclic chemistry, namely 1H-pyrazolo[3,4-b]pyridin-3-ylguanidine was successfully prepared by selective guanylation of 1H-pyrazolo[3,4-b]pyridin-3-amine. A series of 3,4-dihydropyrido[2',3':3,4]pyrazolo[1,5-a][1,3,5]triazin-2-amines was synthesized from 1H-pyrazolo[3,4-b]pyridin-3-ylguanidine using aldehydes or ketones as one-carbon inserting reagents. The tautomeric preferences of the products were determined using spectroscopic (e.g., 2D NOESY NMR) and single crystal X-ray diffraction data.

Full text of DOI:10.1002/jhet.851

Month 2012
Synthesis and Structure of
3,4‐Dihydropyrido[2′,3′:3,4]pyrazolo[1,5‐a][1,3,5]triazin‐2‐amines [1]
a
b
c
b
*
Anton V. Dolzhenko, Shiqi Bai, Anna V. Dolzhenko, and Wai Keung Chui
aFaculty of Health Sciences, School of Pharmacy, Curtin University of Technology, GPO Box
U1987, Perth, Western Australia 6845, Australia
bDepartment of Pharmacy, Faculty of Science, National University of Singapore, 18 Science
Drive 4, Singapore 117543, Singapore
cPerm State Pharmaceutical Academy, 2 Sadovaya Street, Perm 614990, Russian Federation
*
E-mail: Anton.Dolzhenko@curtin.edu.au
Received December 14, 2010
DOI 10.1002/jhet.851
Published online 00 Month 2012 in Wiley Online Library (wileyonlinelibrary.com).
This article is dedicated to Professor Boris Ya. Syropyatov with our best wishes on the occasion of his 70th birthday.
A new convenient synthon for heterocyclic chemistry, namely 1H‐pyrazolo[3,4‐b]pyridin‐3‐ylguanidine
was successfully prepared by selective guanylation of 1H‐pyrazolo[3,4‐b]pyridin‐3‐amine. A series of 3,4‐
dihydropyrido[2′,3′:3,4]pyrazolo[1,5‐a][1,3,5]triazin‐2‐amines was synthesized from 1H‐pyrazolo[3,4‐b]
pyridin‐3‐ylguanidine using aldehydes or ketones as one‐carbon inserting reagents. The tautomeric pre-
ferences of the products were determined using spectroscopic (e.g., 2D NOESY NMR) and single crystal
X‐ray diffraction data.
J. Heterocyclic Chem., 00, 00 (2012).
INTRODUCTION
more interesting group in terms of their biological activity
(viz., antifolate [14,16], antibacterial [13], and anticancer
[12,17] properties).
Pyrazolo[1,5‐a][1,3,5]triazine ring system has been
known since the first report by Checchi and Ridi in 1957
[2] on the synthesis of the compounds with this heterocyclic
core. Now, the pyrazolo[1,5‐a][1,3,5]triazine nucleus is well
recognized as a template for the development of new
heterocyclic molecules with potential therapeutic properties
[3]. However, information on pyrazolo[1,5‐a][1,3,5]triazines
fused with other rings, particularly pyridine ring, is limited.
The available data concerning synthesis of pyrido[2′,3′:3,4]
pyrazolo[1,5‐a][1,3,5]triazines are fragmentary and the
products lack appropriate structural characterization [4–7].
N‐Heterocyles bearing guanidine moiety in the position
vicinal to the endocyclic nitrogen atom are useful building
blocks for the construction of the fused amino‐1,3,5‐triazines.
The annelation of the triazine ring can be achieved via a
cyclocondensation of the heterylguanidines with a variety
of one‐carbon inserting reagents. In our program on the
synthesis of fused 1,3,5‐triazines, this strategy has been
successfully applied for various 1,2,4‐triazol‐5‐yl‐ [8–12],
benzimidazol‐2‐yl‐ [13–18], benzoxazol‐2‐yl‐ [18], benzothiazol‐
2‐yl‐ [18], pyrimidin‐2‐yl‐ [19,20], and quinazolin‐2‐yl‐ [17,21]
substituted guanidines. Among fused 1,3,5‐triazines obtained
by this approach, dihydro‐1,3,5‐triazines appeared to be the
This study is designed with the objective to synthesize a
series of 3,4‐dihydropyrido[2′,3′:3,4]pyrazolo[1,5‐a][1,3,5]
triazines via the cyclocondensation of 1H‐pyrazolo[3,4‐b]
pyridin‐3‐guanidine (3) with carbonyl compounds (i.e.,
aldehydes and ketones). The structural features of the pro-
ducts, particularly tautomeric preferences are also discussed
herein.
RESULTS AND DISCUSSION
1H‐Pyrazolo[3,4‐b]pyridin‐3‐amine (2), required for the
synthesis of guanidine 3, was prepared using previously
reported [22] reaction of 2‐chloro‐3‐cyanopyridine (1) with
hydrazine (Scheme 1). The guanylation of 3 with cyanamide
in the presence of acid proceeded at the exocyclic nitrogen
affording 1H‐pyrazolo[3,4‐b]pyridin‐3‐ylguanidine (3) as a
1
salt. The H NMR spectrum of the hydrochloride of com-
pound 3 contained a broad signal of four protons at 8.05
ppm corresponding to the guanidine group and two deute-
rium oxide exchangeable singlets at 12.05 and 13.56 ppm,
© 2012 HeteroCorporation

A. V. Dolzhenko, S. Bai, A. V. Dolzhenko, and W. K. Chui
Vol 000
The amino group, methine proton at the sp3‐hybridized
carbon, and endocyclic NH signals at 6.43–6.61, 6.81–7.15,
and 7.87–8.11 ppm, respectively (Table 2), appeared in the
regions characteristic for the similar fused aryl‐substituted
dihydro‐1,3,5‐triazines with the primary amino group [8,12–
17,21].
Scheme 1. Synthesis of 1H‐pyrazolo[3,4‐b]pyridin‐3‐ylguanidine (3).
The reaction of guanidine 3 with acetone under catalysis
of piperidine led to the formation of 3,4‐dihydropyrido
[2′,3′:3,4]pyrazolo[1,5‐a][1,3,5]triazin‐2‐amine (6) with
two geminal methyl groups (Scheme 3). Spiro fused analog
7 was prepared similarly by heating 3 with cyclopentanone
in ethanol. The signals in 13C‐NMR spectra at 70.6 and
80.0 ppm (for 6 and 7, respectively) indicated the creation
of quaternary sp3‐hybridized carbon atoms formed due to
the triazine ring annelation.
3,4‐Dihydropyrido[2′,3′:3,4]pyrazolo[1,5‐a][1,3,5]triazines
5, 6, and 7 might be involved in the prototropic annular
tautomerism. Possible migration of the proton from one to
another endocyclic nitrogen atom might result in the exis-
tence of four tautomers: 3,4‐dihydro‐ (A), 1,4‐dihydro‐ (B),
4,6‐dihydro‐ (C), and 4,7‐dihydro‐ (D) forms (Scheme 4).
therefore, suggesting protonation of the endocyclic pyridine
nitrogen rather than the guanidine group of 3. The base
3 is freely soluble in aqueous solutions of strong alkali
(e.g., sodium hydroxide) but can be conveniently isolated
by treatment of salt 3·HCl with aqueous sodium carbonate.
In the piperidine‐catalyzed reaction with pyrazolo[3,4‐b]
pyridin‐3‐ylguanidine (3), aldehydes acted as electrophilic
one‐carbon inserting reagents providing hitherto unknown 4‐
het(aryl)‐3,4‐dihydropyrido[2′,3′:3,4]pyrazolo[1,5‐a][1,3,5]
triazin‐2‐amines (5) (Scheme 2 and Table 1). The signals of
the sp3‐hybridized carbon atom of 5 in 13C‐NMR spectra at
63–70 ppm (Table 2) confirmed that the triazine ring closure
had occurred and ruled out structure 4 (probable intermediate
in the reaction).
Scheme 2. Synthesisof4-(het)aryl-3,4-dihydropyrido[20,30:3,4]pyrazolo[1,5-a][1,3,5]triazin-2-amines(5).
Table 1
4-(Het)aryl-3,4-dihydropyrido[20,30:3,4]pyrazolo[1,5-a][1,3,5]triazin-2-amines (5).
Analysis %, Calcd./Found
Compound
R
mp (ºC)
259–260
239–240
234–235
240–241
243–244
251–252
255–256
217–218
Yield (%)
Molecular Formula
14H12N6
C
H
N
5a
5b
5c
5d
5e
5f
Ph
95
90
88
89
63
79
86
88
C
63.62
63.65
64.73
64.81
61.21
61.04
56.29
56.22
56.69
56.48
53.32
53.20
58.86
58.83
58.86
58.78
4.58
4.60
5.07
5.10
4.79
4.83
3.71
3.80
3.96
4.03
3.73
3.77
4.18
4.23
4.18
4.28
31.80
31.67
30.20
30.03
28.55
28.32
28.13
28.01
33.05
32.98
31.09
31.00
36.96
36.88
36.96
36.72
4-MeC6H4
4-MeOC6H4
4-ClC6H4
2-Furyl
C15H14N6
C15H14N6O
C14H11ClN6
C12H10N6O
C12H10N6S
C13H11N7
2-Thienyl
2-Pyridyl
4-Pyridyl
5g
5h
C13H11N7
Journal of Heterocyclic Chemistry
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Month 2012 Synthesis and Structure of 3,4‐Dihydropyrido[2′,3′:3,4]pyrazolo[1,5‐a][1,3,5]triazin‐2‐amines
Table 2
Spectral data of 4‐(het)aryl‐3,4‐dihydropyrido[2′,3′:3,4]pyrazolo[1,5‐a][1,3,5]triazin‐2‐amines (5).
Dimethyl sulfoxide‐d6/TMS, δ (ppm)
Compound
1H‐NMR (300 MHz)
13C‐NMR (75 MHz)
5a
6.52 (2H, s, NH2), 6.79 (1H, dd, 3 J = 8.1, 3J = 4.3 Hz, H‐9),
6.89 (1H, s, H‐4), 7.27–7.44 (5H, m, Ph), 7.96 (1H, dd,
3J = 8.1, 4J = 1.8 Hz, H‐10), 8.01 (1H, s, NH), 8.41 (1H,
dd, 3J = 4.3, 4 J = 1.8 Hz, H‐8)
69.0 (C‐4), 103.4 (C‐10a), 113.7 (C‐9), 126.1 (C‐2′
and C‐6′), 128.6 (C‐3′ and C‐5′), 128.8 (C‐4′),
130.1 (C‐10), 140.6, 140.7 (C‐10b and C‐1′),
151.3 (C‐8), 153.1 (C‐6a), 157.4 (C‐2)
20.6 (Me), 68.8 (C‐4), 103.4 (C‐10a), 113.6 (C‐9), 126.0
(C‐2′ and C‐6′), 129.0 (C‐3′ and C‐5′), 130.0 (C‐10),
137.9 (C‐4′), 138.2 (C‐1′), 140.5 (C‐10b), 151.2 (C‐8),
153.1 (C‐6a), 157.3 (C‐2)
3
5b
5c
2.28 (3H, s, Me), 6.44 (2H, s, NH2), 6.78 (1H, dd, J = 8.3,
3J = 4.1 Hz, H‐9), 6.82 (1H, d, 3J = 1.9 Hz, H‐4),
3
7.15–7.23 (4H, m, C6H4), 7.90 (1H, d, J = 1.8 Hz, NH),
3
7.94 (1H, dd, J = 8.3, 4J = 1.5 Hz, H‐10), 8.40 (1H, dd,
3J = 4.1, 4J = 1.5 Hz, H‐8)
3.73 (3H, s, OMe), 6.43 (2H, s, NH2), 6.77 (1H, dd, 3J = 8.3,
3J = 4.1 Hz, H‐9), 6.81 (1H, d, 3J = 1.5 Hz, H‐4), 6.94
55.1 (OMe), 68.7 (C‐4), 103.4 (C‐10a), 113.6 (C‐9), 113.9
(C‐3′ and C‐5′), 127.5 (C‐2′ and C‐6′), 130.0 (C‐10),
132.9 (C‐1′), 140.5 (C‐10b), 151.2 (C‐8), 153.1 (C‐6a),
157.3 (C‐2), 159.6 (C‐4′)
3
(2H, d, 3J = 8.7 Hz, H‐3′ and H‐5′), 7.23 (2H, d,
J = 8.7 Hz, H‐2′ and H‐6′), 7.87 (1H, d, 3 J = 1.5 Hz, NH),
7.93 (1H, dd, J = 8.3, 4J = 1.8 Hz, H‐10), 8.39 (1H, dd,
3
3J = 4.1, 4J = 1.8 Hz, H‐8)
3
5d
6.50 (2H, s, NH2), 6.79 (1H, dd, 3J = 8.3, J = 4.1 Hz, H‐9),
68.2 (C‐4), 103.4 (C‐10a), 113.8 (C‐9), 128.0, 128.6 (C‐2′
and C‐6′ and C‐3′ and C‐5′), 130.0 (C‐10), 133.3 (C‐4′),
139.6 (C‐1′), 140.6 (C‐10b), 151.4 (C‐8), 153.0 (C‐6a),
157.4 (C‐2)
6.91 (1H, d, 3J = 1.9 Hz, H‐4), 7.31 (2H, d, 3J =
8.5 Hz, H‐2′ and H‐6′), 7.48 (2H, d, 3J = 8.5 Hz, H‐3′
and H‐5′), 7.94 (1H, dd, 3J = 8.3, 4J = 1.5 Hz, H‐10),
7.97 (1H, d, 3J = 1.8 Hz, NH), 8.41 (1H, dd, 3J = 4.1,
4J = 1.8 Hz, H‐8)
5e
5f
δ 6.39–6.56 (4H, m, NH2, H‐3′, and H‐4′), 6.78 (1H, dd,
3J = 8.3, 3J = 4.1 Hz, H‐9), 6.95 (1H, s, H‐4), 7.64 (1H,
s, H‐5′), 7.87–7.99 (2H, m, H‐10 and NH), 8.41 (1H, dd,
3J = 4.1, 4J = 1.9 Hz, H‐8)
63.0 (C‐4), 103.4 (C‐10a), 108.4, 110.4 (C‐3′ and C‐4′),
113.7 (C‐9), 130.0 (C‐10), 140.6 (C‐10b), 143.6 (C‐5′),
151.4 (C‐8), 151.9 (C‐2′), 153.1 (C‐6a), 157.4 (C‐2)
3
6.54 (2H, s, NH2), 6.79 (1H, dd, 3J = 7.9, J = 4.1 Hz, H‐9),
65.1 (C‐4), 103.5 (C‐10a), 113.8 (C‐9), 125.9, 126.6, 127.2
(C‐3′, C‐4′, and C‐5′), 130.0 (C‐10), 140.1 (C‐10b), 143.9
(C‐2′), 151.4 (C‐8), 152.9 (C‐6a), 157.4 (C‐2)
7.01 (1H, dd, 3J = 4.9, 3J = 3.8 Hz, H‐4′), 7.14–7.22
(2H, m, H‐4 and H‐3′), 7.53 (1H, dd, 3J = 5.3,
4J = 0.8 Hz, H‐5′), 7.93 (1H, dd, 3J = 8.3, 4J = 1.9 Hz,
H‐10), 8.08 (1H, s, NH), 8.42 (1H, dd, 3J = 4.1, 4J =
1.9 Hz, H‐8)
3
5g
5h
6.45 (2H, s, NH2), 6.79 (1H, d, 3 J = 8.3, J = 4.1 Hz, H‐9),
69.9 (C‐4), 103.5 (C‐10a), 113.6 (C‐9), 120.9 (C‐3′), 124.1
(C‐5′), 130.1 (C‐10), 137.3 (C‐4′), 141.1 (C‐10b), 149.4
(C‐6′), 151.4 (C‐8), 153.1 (C‐6a), 157.3 (C‐2), 158.3 (C‐2′)
3
6.88 (1H, d, 3J = 1.9 Hz, H‐4), 7.18 (1H, d, J = 7.9 Hz,
H‐3′), 7.39 (1H, dd, 3 J = 7.5, 3 J = 4.9 Hz, H‐5′), 7.82
(1H, td, 3J = 7.6, 4J = 1.6 Hz, H‐4′), 7.96 (1H, dd, 3J = 8.3,
3
4J = 1.5 Hz, H‐10), 8.03 (1H, d, J = 1.9 Hz, NH), 8.41
4
3
(1H, dd, 3J = 4.1, J = 1.9 Hz, H‐8), 8.57 (1H, d, J =
4.5 Hz, H‐6′)
6.61 (2H, s, NH2), 6.81 (1H, dd, 3 J = 8.1, 3J = 4.1 Hz, H‐9),
67.7 (C‐4), 103.4 (C‐10a), 113.9 (C‐9), 120.8 (C‐3′
and C‐5′), 130.1 (C‐10), 140.8 (C‐10b), 148.4 (C‐4′),
150.1 (C‐2′ and C‐6′), 151.6 (C‐8), 153.0 (C‐6a),
157.5 (C‐2)
4
6.96 (1H, s, H‐4), 7.27 (2H, dd, 3 J = 4.3, J = 1.5 Hz, H‐3′
and H‐5′), 7.96 (1H, dd, 3J = 8.1, 4J = 1.7 Hz, H‐10), 8.11
(1H, s, NH), 8.44 (1H, dd, 3J = 4.1, 4J = 1.7 Hz, H‐8), 8.61
4
(2H, dd, 3J = 4.3, J = 1.5 Hz, H‐2′ and H‐6′)
The coupling of the H‐4 and NH signals (3J = 0–1.9 Hz) in
1H NMR spectra of 5 suggested the equilibrium to be shifted
toward 3,4‐dihydro‐tautomeric form A. In a 2D NOESY
experiment conducted on 6, a strong pair of cross‐peaks
was observed for the gem‐dimethyl signal at 1.72 ppm and
the N H signal at 7.62 ppm. The close spatial relationship
of the methyl groups and the proton at annular nitrogen atom
might correspond to the 3,4‐dihydro‐ (A) or 4,6‐dihydro‐ (C)
tautomeric forms. X‐ray crystallographic study [23] on 6 was
performed to differentiate between these two tautomers. The
crystals suitable for X-ray diffraction analysis were obtained
by recrystallization of 6 from ethanol. The molecule of 6
crystallized together with one ethanol molecule, therefore
providing the ethanol monosolvate of 6. Similarly to the
previously reported [10,24] fused gem‐dimethyl substituted
amino‐1,3,5‐triazines, 6 existed in the crystal as a tautomer
with the labile hydrogen atom located at the triazine nitro-
gen atom adjacent to the quaternary sp3‐hybridized carbon
atom (Fig. 1). Considering the similarity of the spectral
data for 5–7, we concluded that 3,4‐dihydro‐tautomeric
form A was generally preferred in solution and solid states
for all series of the compounds.
Pyrido[2′,3′:3,4]pyrazolo[1,5‐a][1,3,5]triazines 5–7 un-
derwent a series of biological screening assays. They showed
Journal of Heterocyclic Chemistry
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A. V. Dolzhenko, S. Bai, A. V. Dolzhenko, and W. K. Chui
Vol 000
Scheme 3. Reaction of 1H‐pyrazolo[3,4‐b]pyridin‐3‐ylguanidine (3)
with ketones.
EXPERIMENTAL
Melting points (uncorrected) were determined on a Gallenkamp
melting point apparatus. Analytical thin layer chromatography
(TLC) was carried out on aluminum plates coated with silica gel
1
60 F254 (Merck) with detection by UV light. H‐ and 13C‐NMR
spectra were recorded on a Bruker DPX‐300 spectrometer in the
dimethyl sulfoxide‐d6 (DMSO‐d6) solution using tetramethylsilane
(TMS) as an internal reference. Assignments were done on the basis
of 2D 1H–1H COSY, 1H–13C HMQC, and NOESY experiments.
1H‐Pyrazolo[3,4‐b]pyridin‐3‐amine (2).
The mixture of
2‐chloro‐3‐cyanopyridine (1, 6.93 g, 50 mmol) and hydrazine
hydrate (80%, 6.2 mL, 100 mmol) in ethanol (60 mL) was
heated under reflux with stirring for 6 h. After cooling at 4 °C,
the precipitated product was filtered, washed with cold ethanol,
dried and recrystallized from ethanol to give 5.76 g (86%)
of 2; mp: 183–184 °C [ref. 22; mp: 184–185 °C]; 1H‐NMR
(300 MHz, DMSO‐d6): δ 6.33 (2H, br s, NH2), 6.96 (1H, dd,
neither appreciable antiproliferative activity against MDA‐
MB‐231 breast cancer cell line nor dihydrofolate reductase
inhibitory activity. They were also found to be inactive in
the ApoE secretion, cell cycle, anti‐angiogenesis, insulin
secretion, and Wnt pathway Eli Lilly’s phenotypic bioassay
modules.
In conclusion, a series of new 3,4‐dihydropyrido[2′,3′:3,4]
pyrazolo[1,5‐a][1,3,5]triazines 5‐7 was successfully synthe-
sized using cyclocondensation of 1H‐pyrazolo[3,4‐b]pyridin‐
3‐ylguanidine (3) with carbonyl compounds. The developed
method is general, and a variety of aldehydes and ketones
can be applied as one‐carbon inserting reagents for the
triazine ring annelation. The products 5–7 appear to exist
as the 3,4‐dihydro‐tautomers in the solution and solid state.
3
3
4
3J = 7.9, J = 4.5 Hz, H‐5), 8.15 (1H, dd, J = 7.9, J = 1.5 Hz,
3
4
H‐4), 8.35 (1H, dd, J = 4.5, J = 1.5 Hz, H‐6), 11.88 (1H, br s,
NH); 13C‐NMR (75 MHz, DMSO‐d6): δ 106.1 (C‐3a), 113.7
(C‐5), 129.6 (C‐4), 148.0 (C‐3), 148.4 (C‐6), 152.3 (C‐7a).
1H‐Pyrazolo[3,4‐b]pyridin‐3‐ylguanidine (3). To the solution
of 1H‐pyrazolo[3,4‐b]pyridin‐3‐amine (2, 4.20 g, 30 mmol) and
cyanamide (1.39 g, 30 mmol) in ethanol (25 mL), concentrated
hydrochloric acid (3 mL, 30 mmol) was added and the reaction
mixture was heated under reflux with stirring for 6 h. After cooling,
the precipitated 1H‐pyrazolo[3,4‐b]pyridin‐3‐ylguanidine hydrochloride
was filtered, washed with cold ethanol, and dried. Free base 3 was
obtained by treatment of aqueous solution of pyrazolo[3,4‐b]
pyridin‐3‐ylguanidine hydrochloride with 10% sodium carbonate
solution (30 mL) with stirring and gentle heating at 40–50 °C for
10 min. After cooling, the precipitated product 3 (3.8 g, 72%) was
filtered, washed with cold water, dried and used in the subsequent
reactions without further purification. Analytical sample was
Scheme 4. Possible tautomeric forms of 3,4-dihydropyrido [20,30:3,4]
pyrazolo[1,5-a][1,3,5]triazin-2-amines (annular tautomerism).
Figure 1. Molecular structure of 4,4‐dimethyl‐3,4‐dihydropyrido
[2′,3′:3,4]pyrazolo[1,5‐a][1,3,5]triazin‐2‐amine (6) as an ethanol mono-
solvate. Displacement ellipsoids are drawn at the 50% probability level.
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Month 2012 Synthesis and Structure of 3,4‐Dihydropyrido[2′,3′:3,4]pyrazolo[1,5‐a][1,3,5]triazin‐2‐amines
1
obtained by recrystallization from ethanol; mp: 256–257 °C; H‐
NMR (300 MHz, DMSO‐d6): δ 6.55 (4H, br s, NHC( NH)NH2),
Acknowledgments. The authors thank Tan Geok Kheng and
Koh Lip Lin for the X‐ray crystallographic data.
7.00 (1H, dd, 3J = 7.5, J = 4.5 Hz, H‐5), 8.05 (1H, dd, 3J = 7.5,
3
4J = 1.1 Hz, H‐4), 8.39 (1H, dd, 3J = 4.5, 4J = 1.1 Hz, H‐6), 12.38
(1H, br s, NH); 13C‐NMR (75 MHz, DMSO‐d6): δ 110.7 (C‐3a),
114.6 (C‐5), 129.5 (C‐4), 148.6 (C‐6), 151.1 (C‐3), 151.8 (C‐7a),
156.0 (NHC( NH)NH2); Anal. Calcd. for C7H8N6: C, 47.72; H,
4.58; N, 47.70. Found: C, 47.64; H, 4.60; N, 47.72.
REFERENCES AND NOTES
[1] Part 18 in the series “Fused heterocyclic systems with
s‐triazine ring,” for part 17, see: Dolzhenko, A. V.; Tan, G. K.;
Dolzhenko, A. V.; Koh, L. L.; Chui, W. K. Acta Crystallogr
2011, E67, o85.
[2] Checchi, S.; Ridi, M. Gazz Chim Ital 1957, 87, 597.
[3] For review on the synthesis and biological activity of
pyrazolo[1,5‐a][1,3,5]triazines, see: Dolzhenko, A. V.; Dolzhenko, A. V.;
Chui, W. K. Heterocycles 2008, 75, 1575.
General procedure for preparation of 4‐(Het)aryl‐3,4‐
dihydropyrido[2′,3′:3,4]pyrazolo[1,5‐a][1,3,5]triazin‐2‐amines
(5). To the solution of 1H‐pyrazolo[3,4‐b]pyridin‐3‐ylguanidine
(3, 0.88 g, 5 mmol) and appropriate (het)arylaldehyde (5 mmol) in
ethanol (15 mL), piperidine (0.30 mL, 3 mmol) was added and the
mixture was heated under reflux with stirring for 3–16 h. After
cooling, the precipitated product was filtered, washed with cold
ethanol, dried and recrystallized from ethanol.
[4] Youssef, M. M.; Al‐Haiza, M. A. Egypt J Chem 2000, 43, 165.
[5] El‐Dean, A. M. K.; Atalla, A. A.; Gaber, A. M. Bull Fac Sci,
Assiut Univ 1990, 19, 23.
4,4‐Dimethyl‐3,4‐dihydropyrido[2′,3′:3,4]pyrazolo[1,5‐a]
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[1,3,5]triazin‐2‐amine (6).
To the solution of 1H‐pyrazolo
[3,4‐b]pyridin‐3‐ylguanidine (3, 0.88 g, 5 mmol) in acetone
(30 mL), piperidine (0.30 mL, 3 mmol) was added and the
mixture was heated under reflux with stirring for 10 h. After
cooling, the precipitated product was filtered, washed with cold
acetone, dried and recrystallized from ethanol to give 0.84 g
(78%) of 6; mp: 285–286 °C; 1H NMR (300 MHz, DMSO‐d6): δ
1.72 (6H, s, Me2), 6.28 (2H, s, NH2), 6.77 (1H, dd, 3J = 8.3, 3J =
3
4
4.1 Hz, H‐9), 7.62 (1H, s, NH), 7.89 (1H, dd, J = 8.3, J = 1.9
3
4
Hz, H‐10), 8.42 (1H, dd, J = 4.1, J = 1.9 Hz, H‐8); 13C‐NMR
(75 MHz, DMSO‐d6): δ 28.6 (Me2), 70.6 (C‐4), 103.5 (C‐10a),
113.4 (C‐9), 129.9 (C‐10), 139.8 (C‐10b), 150.9 (C‐8), 153.4
(C‐6a), 157.0 (C‐2); Anal. Calcd. for C10H12N6: C, 55.54; H,
5.59; N, 38.86. Found: C, 55.61; H, 5.60; N, 38.73.
4,4‐Tetramethylene‐3,4‐dihydropyrido[2′,3′:3,4]pyrazolo
[1,5‐a][1,3,5]triazin‐2‐amine (7).
To the solution of 1H‐
pyrazolo[3,4‐b]pyridin‐3‐ylguanidine (3, 0.88 g, 5 mmol) and
cyclopentanone (0.51 mL, 5.5 mmol) in ethanol (10 mL),
piperidine (0.30 mL, 3 mmol) was added and the mixture was
heated under reflux with stirring for 16 h. After cooling, the
precipitated product was filtered, washed with cold ethanol, dried
and recrystallized from ethanol to give 0.75 g (62%) of 7;
248–249 °C; 1H‐NMR (300 MHz, DMSO‐d6): δ 1.73–2.01
(6H, m, (CH2)2, H‐1′ax, and H‐4′ax), 2.36–2.49 (2H, m, H‐1′
eq and H‐4′eq), 6.24 (2H, s, NH2), 6.76 (1H, dd, 3J = 8.2,
3J = 4.1 Hz, H‐9), 7.72 (1H, s, NH), 7.89 (1H, dd, 3J = 8.1,
4J = 1.0 Hz, H‐10), 8.41 (1H, dd, 3J = 4.0, 4J = 1.1 Hz,
H‐8); 13C‐NMR (75 MHz, DMSO‐d6): δ, 23.4 (C‐1′ and
C‐4′), 39.8 (C‐2′ and C‐3′), 80.0 (C‐4), 103.6 (C‐10a), 113.5
(C‐9), 129.8 (C‐10), 140.5 (C‐10b), 150.9 (C‐8), 153.5 (C‐6a),
157.0 (C‐2); Anal. Calcd. for C12H14N6: C, 59.49; H, 5.82; N,
34.69. Found: C, 59.35; H, 5.90; N, 34.64.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet