Synthesis of new pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines and related heterocycles

Article abstract of DOI:10.1016/j.tet.2004.04.010

The reaction between 5-amino-4-imino-1(2)-substituted-1(2)H-4,5- dihydropyrazolo[3,4-d]pyrimidines and several commercially available reactants afforded new heterocycles with a conserved pyrazolo[3,4-d]pyrimidine nucleus. The key intermediates employed proved to be suitable compounds by virtue of their two vicinal amino and imino groups that were used to obtain five, six and seven-membered rings.

Full text of DOI:10.1016/j.tet.2004.04.010

Tetrahedron 60 (2004) 5093–5104
Synthesis of new pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines
and related heterocycles
b
b
c
Pier Giovanni Baraldi,a Hussein El-Kashef, Abdel-Rahman Farghaly, Patrice Vanelle
,
*
and Francesca Fruttaroloa
a
`
Dipartimento di Scienze Farmaceutiche, Universita di Ferrara, Via Fossato di Mortara 17-19, 44100 Ferrara, Italy
bDepartment of Chemistry, Faculty of Science, Assiut University, 71516 Assiut, Egypt
´
Laboratoire de Chimie Organique, UMR CNRS 6517, Faculte de Pharmacie, 27 Boulevard Jean Moulin, 13385 Marseille Cedex 5, France
c
Received 3 November 2003; revised 8 March 2004; accepted 1 April 2004
Abstract—The reaction between 5-amino-4-imino-1(2)-substituted-1(2)H-4,5-dihydropyrazolo[3,4-d]pyrimidines and several com-
mercially available reactants afforded new heterocycles with a conserved pyrazolo[3,4-d]pyrimidine nucleus. The key intermediates
employed proved to be suitable compounds by virtue of their two vicinal amino and imino groups that were used to obtain five, six and seven-
membered rings.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
pyrazolo[1,5-c]-1,2,4-triazolo[4,3-e]pyrimidine structure,
N7-substituted for molecules designed as A2A antagonists
and N8-substituted for molecules planned as A3
antagonists.5–14 Until now, the best results in terms of
A2A and A3 antagonistic affinity and selectivity are
respectively achieved by the synthesis of SCH 582615 and
the 5-N-(substituted-phenylcarbamoyl)amino-N8-substituted-
pyrazolo-triazolo-pyrimidines, belonging to MRE analogs
(Fig. 1).10,11 Along with the tricyclic structure, another
structural requirement necessary for the activity and, above
all, the receptor anchorage was found to be the presence of the
2-furyl group at the 2-position of the tricyclic core.5
Adenosine is present in different tissues in the mammalian
organism where it has a variety of important physiological
functions such as the synthesis of nucleic acids or
implications in energy metabolism production.1–3 Adeno-
sine interacts with four cell surface receptor subtypes (ARs)
classified as A1, A2A, A2B and A3, belonging to the family of
G protein-coupled receptors.4 Efforts made in medicinal
chemistry in the past 20 years have led to the discovery of a
variety of selective antagonists for the A2A and the A3
adenosine receptor subtypes. Among these, it was demon-
strated that the structural requirement for reaching A2A and
A3 antagonist behavior is the tricyclic heterocyclic
Starting from these SAR observations and in continuation to
Figure 1. Potent and selective A2A and A3 adenosine receptor antagonists.
Keywords: Reactivity studies; Adenosine antagonists; Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines; 5-Amino-4-imino-1(2)-substituted-1(2)H-
pyrazolo[3,4-d]pyrimidines.
*
Corresponding author. Tel.: þ39-0532-291293; fax: þ39-0532-291296; e-mail address: pgb@dns.unife.it
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.04.010

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P. G. Baraldi et al. / Tetrahedron 60 (2004) 5093–5104
the aim of obtaining new heterocycles with a conserved
pyrazolo[3,4-d]pyrimidine core. The substituents selected
for the pyrazole nitrogen of 4a–c were mainly 1-phenyl but
1-(2-phenylethyl) like SCH 58261, and 2-methyl like the
MRE series were also chosen for comparison reasons.
In our chemical reactivity studies described here, we
principally employed the intermediate 4a (5-amino-4-
imino-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine), due to its
easy preparation, high reactivity and good yield of reactions.
The major limitations of compounds 4b and 4c were their
low solubility in organic solvents employed in the clusters
of reactions performed and, at the same time, the restricted
yield of reactions.
The new heterocycles obtained will be evaluated in
pharmacological assays to determine their antagonist
properties versus the A2A and A3 adenosine receptor
subtypes.
Scheme 1.
our interest in the synthesis of pyrazolo[4,3-e]-1,2,4-
triazolo[1,5-c]pyrimidines15 we decided to design and
synthesize new adenosine ligands, maintaining the pyra-
zolo[3,4-d]pyrimidine nucleus and to replace the 2-(2-
furyl)-triazole moiety with other five, six and seven-
membered rings, fused to the pyrazolo[3,4-d]pyrimidine
ring system and functionalized by the introduction of
several functions, such as ester, acid, amide, hydrazide, and
alkyl groups.
2. Results and discussions
The N1 or N2-substituted amino-cyano-pyrazoles16,17 were
reacted with triethylorthoformate to give the corresponding
ethoxymethylene amino derivatives 3a–c. These latter
compounds were used as intermediates for the preparation
of the key compounds 4a–c by cyclization with hydrazine
hydrate, as depicted in Scheme 1.
When 4a was allowed to react with CS2, the pyrazolo-
triazolo-pyrimidine-2-thione 5 was obtained. This latter
compound, was alkylated using several alkylating agents
(RX) in refluxing ethanol in the presence of anhydrous
sodium acetate to give the corresponding derivatives 6a–j.
The Mannich bases 7a–c were obtained via the reaction of
the thione 5 with formaldehyde and the corresponding
amines. In a trial to prepare the hydrazino derivative via the
For this purpose we started from the key intermediates 4a–c
(5-amino-4-imino-1(2)-substituted-1(2)H-pyrazolo[3,4-
d]pyrimidines), easily obtained from the N1 or N2-
substituted amino-cyano-pyrazoles (Scheme 1).16,17 These
substrates proved to be versatile compounds by virtue of
their vicinal amino and imino functions, evaluating the
reactivity in several cyclization reactions performed with
Scheme 2.

P. G. Baraldi et al. / Tetrahedron 60 (2004) 5093–5104
5095
Scheme 3.
reaction of 5 with hydrazine hydrate, unexpectedly the
reaction product was found to be compound 4a (Scheme 2).
cyclized into 16 in boiling POCl3. Interestingly, upon
warming 4a in diethyl oxalate the intermediate 18 was
obtained. This upon heating in boiling POCl3 gave the ester
19. Alternatively, compound 19 could be obtained directly
from 4a by heating under reflux with diethyl oxalate and no
evidence for the formation of the possible dioxotriazine
derivate 17a was observed.
As described in Scheme 3, reaction of 4a with triethyl-
orthoformate afforded the corresponding 7-phenyl-7H-
pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine 8; however,
its reaction with ethyl formate did not afford 8 but gave the
intermediate formylamino derivative 8a which could be ring
closed in refluxing phosphoryl chloride to give 8. Other
2-substituted derivatives of 8 could be synthesized as shown
in Scheme 3. The 2-methyl derivative 9 was obtained by
boiling 4a in glacial acetic acid. However, upon heating
compound 4a in refluxing acetic anhydride the reaction
product was identified as the triacetyl derivative 12 and not
the expected product 9. Compound 11 (the 2-phenyl analog
of 9) could not be obtained directly by the reaction of 4a
with benzoylchloride which gave the benzoylamino deriva-
tive 10. This latter compound could be cyclized into 11 in
boiling POCl3 (Scheme 3).
Interestingly, hydrazinolysis of the ester 19 did not afford
the expected carbohydrazide derivative 20 but resulted in
ring opening of the triazole ring giving back the amino-
imino compound 4a.
In Scheme 5, reaction of 4a with an excess of diethyl
malonate gave directly the ester 23. As was the case with
compound 19, hydrazinolysis of compound 23 did not afford
the expected hydrazide derivative but also resulted in
opening of the triazole ring with the formation of the
aminoimino compound 4a. The interaction of compounds
4a–c with an equimolar ratio of ethyl chloroformate gave
the corresponding triazino derivative 21a–c, whereas the
reaction of 4a with an excess of same reagent gave the
diethoxycarbonylamino compound 22. When compound 4a
was subjected to the diazotization reaction conditions, the
tetrazolo derivative 24 was formed.
On the other hand, as depicted in Scheme 4, the
2-phenylamino derivative 14 was obtained when 4a was
treated with phenylisothiocyanate in refluxing pyridine.
Obviously this reaction proceeded via the thiourea inter-
mediate 13 with concomitant dehydrosulfurization. Also,
the reaction of 4a with chloroacetyl chloride did not afford
the chloromethyl derivative 16 but resulted in the formation
of chloroacetylamino derivative 15, which could not be
Treatment of compounds 4a–c with oxalyl chloride in
refluxing dry benzene afforded the corresponding dioxo-

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P. G. Baraldi et al. / Tetrahedron 60 (2004) 5093–5104
Scheme 4.
triazine compounds 17a–c. However, reaction of 4a with
pyruvic acid gave the intermediate 25, which was cyclized
in boiling POCl3 to give the triazinone compound 26
(Scheme 5).
to those obtained for 9. The NMR spectrum of the products
formed from the reaction between 4a–c and acetylacetone
(compounds 27a–c) showed two additional methyl signals.
This is in agreement with the structure of 5,7-dimethyl-1(2)-
substituted-1(2)H-azolo[30,40:4,5]pyrimido[1,6-b]triaze-
pines 27a–c. It is noteworthy that when the reaction was
carried out with 4a in benzoylacetone, the product was
identified as the intermediate azomethine compound 28
which could be cyclized to the corresponding triazepine 29
by heating in refluxing phosphoryl chloride (Scheme 6). The
reaction between 4a and ethyl benzoylacetate led to
the formation of the triazepine 31. On the other hand the
reaction of 4a with ethoxymethylenemalononitrile or ethyl
ethoxymethylenecyano-acetate did not afford the triazolo
derivative 8, as would be expected from the same reaction
reported for the amino-imino derivative of the thieno-
pyrimidine,18 however the reaction products were identified
In a comparative study,18 it was reported that the reaction of
the 3-amino-4-imino-3,4-dihydrothieno[2,3-d]pyrimidine
with acetylacetone gave 2-methythieno[3,2-e]-[1,2,4]tri-
azolo[1,5-c]pyrimidine and its reaction with ethoxymethyl-
enemalononitrile or ethyl ethoxymethylenecyanoacetate led
to the formation of the parent thieno[3,2-e] [1,2,4]tri-
azolo[1,5-c]pyrimidine.
In contrast, in our hands when the aminoimino compound
4a was allowed to react with acetylacetone under the same
reaction conditions reported for the reaction described
above we got a product with a different mp and spectral data

P. G. Baraldi et al. / Tetrahedron 60 (2004) 5093–5104
5097
Scheme 5.
as the triazepine–aminonitrile and aminoester derivatives
30a,b, respectively. Compound 32 was finally obtained
from the reaction between 4a and benzoylacetonitrile.
A2A and A3 adenosine receptor subtypes will be the subject
of another publication.
In conclusion, the amino ester 30b could be hydrolyzed to
the corresponding amino acid 30c, however, the hydra-
zinolysis of the ester function of 30b did not lead to the
corresponding amino hydrazide derivative but gave back the
amino imino derivative 4a.
4. Experimental
4.1. General
Reactions were routinely monitored by thin-layer chroma-
tography (TLC) on silica gel (precoated F245 Merck plates)
and products visualized with iodine or potassium per-
1
manganate solution. H NMR spectra were determined in
3. Conclusion
CDCl3, CF3COOD or DMSO-d6 solutions with a Bruker AC
200 spectrometer. Peak positions are given in parts per
million (d) downfield from tetramethylsilane as internal
standard, and J values are given in Hz. IR spectra were
recorded on Pye Unicam SP 300 spectrometer using KBr
Wafer technique. Mass spectra were obtained with a
Shimadzu QP5050 DI 50 spectrometer. Light petroleum
ether refers to the fractions boiling at 40–60 8C. Melting
points were determined on a Buchi–Tottoli instrument and
are uncorrected. Chromatographies were performed using
Merck 60–200 mesh silica gel. All products reported
New heterocycles were obtained from the reaction between
5-amino-4-imino-1(2)-substituted-1(2)H-4,5-dihydropyra-
zolo[3,4-d]pyrimidines 4a–c and several commercially
available reactants. All the compounds obtained and
described in this work retain the pyrazolopyrimidine core
while third fused heterocyclic nucleus (five, six or seven-
membered) was constructed via easily accessible
intermediates. A SAR study of the newly synthesized
compounds to evaluate their affinity and selectivity toward

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P. G. Baraldi et al. / Tetrahedron 60 (2004) 5093–5104
Scheme 6.
1
showed H NMR spectra in agreement with the assigned
structures. Analyses were performed by the micro-analyti-
cal laboratory of Dipartimento di Chimica, University of
Ferrara. Compounds 3a–c were prepared according to
known procedures.16,17
zolo[3,4-d]pyrimidine 4b. Yield 66% (3.27 g), white
crystals, mp 264 8C. [Found: C, 61.33; H, 5.24; N, 32.88.
C13H14N6 requires: C, 61.40; H, 5.55; N, 33.05]. IR cm21
:
3260, 3180 (NH and NH2), 1590 (CvN); 1H NMR DMSO-
d6): d 3.14 (t, 2H, CH2, J¼7.2 Hz), 4.49 (t, 2H, CH2,
J¼7.2 Hz), 4.82 (bs, 2H, NH2), 7.12–7.23 (m, 5H, phenyl),
8.03 (s, 1H, CH-pyrazole), 8.28 (s, 1H, CH-pyrimidine),
9.07 (s, 1H, NH). MS: m/z 255.2 (Mþ).
4.1.1. General procedures for the preparation of
5-amino-4-imino-1(2)-substituted-1(2)H-4,5-dihydro-
pyrazolo[3,4-d]pyrimidines 4a–c.
A
mixture of
compounds 3a–c (5.24 g, 22 mmol) and hydrazine hydrate
(8 mL, 80%) in ethanol (20 mL) was heated under reflux for
2 h. The white precipitate formed after cooling was filtered
off and dried. Recrystallization from ethanol afforded the
required products 4a–c as white crystals.
5-Amino-4-imino-2-methyl-2H-4,5-dihydropyrazolo[3,4-
d]pyrimidine 4c. Yield 45% (1.95 g), white crystals, mp
.300 8C. [Found: C, 43.79; H, 4.80; N, 50.98. C6H8N6
requires: C, 43.90; H, 4.91; N, 51.19]. IR cm21: 3320, 3210
(NH and NH2), 1615 (CvN); 1H NMR (DMSO-d6): d
3.74)s, 3H, CH3), 6.56 (bs, 2H, NH2), 7.98 (s, 1H, CH-
pyrazole), 8.20 (s, 1H, CH-pyrimidine), 11.78 (s, 1H, NH).
MS: m/z 165.2 (Mþ).
5-Amino-4-imino-1-phenyl-1H-4,5-dihydropyrazolo[3,4-
d]pyrimidine 4a. Yield 78% (3.84 g), white crystals, mp
235 8C. [Found: C, 58.56; H, 4.35; N, 37.10. C11H10N6
requires: C, 58.39; H, 4.46; N, 37.15]. IR cm21: 3330, 3200
(NH and NH2), 1630 (CvN); 1H NMR (DMSO-d6): d 4.90
(s, 2H, NH2), 7.63–7.17 (m, 5H, phenyl), 8.23 (s, 1H,
CH-pyrazole), 8.30 (s, 1H, CH-pyrimidine), 9.43 (s, 1H,
NH). MS: m/z 226.24 (Mþ).
4.1.2. 7-Phenyl-7H-2,3-dihydro-2-thioxopyrazolo[4,3-e]-
[1,2,4]triazolo[1,5-c]pyrimidine 5. To a stirred suspension
of compound 4a (5.24 g, 22 mmol) in ethanol (20 mL),
ethanolic potassium hydroxide (30 mL, 0.01 mol) and CS2
(2 mL) were added dropwise. The reaction mixture was then
heated under reflux for 6 h. After cooling and evaporation of
the solvent, the potassium salt obtained was dissolved in
5-Amino-4-imino-1-(2-phenylethyl)-1H-4,5-dihydropyra-

P. G. Baraldi et al. / Tetrahedron 60 (2004) 5093–5104
5099
water and acidified with 2 N aqueous HCl. The solid product
formed was collected and recrystallized from ethanol into
yellow crystals. Yield 0.30 g (75%), mp 275–277 8C.
[Found: C, 53.50; H, 3.36; N, 31.19. C12H8N6S requires:
C, 53.72; H, 3.01; N, 31.33]. IR; cm21 3350 (NH), 1630
(CvN), 1190 (CvS). 1H NMR (DMSO-d6): d 7.55 (m, 3H,
phenyl), 7.93–8.13 (m, 2H, phenyl), 8.60 (s, 1H, CH-
pyrazole), 9.03 (s, 1H, CH-pyrimidine), 9.47 (s, 1H, NH).
MS: m/z 268.27 (Mþ).
2-(7-Phenyl-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyri-
midin-2-yl)thio acetamide 6e. Using chloroacetamide 6e
was obtained as fluffy yellow crystals from dioxane. Yield
0.126 g, (39%), mp 255–57 8C. [Found: C, 51.53; H, 3.38;
N, 29.97. C14H11N7SO requires: C, 51.68; H, 3.41; N,
30.14]. IR cm21 3350, 3180 (NH2), 3050 (CH arom.), 2900
1
(CH aliph.), 2220 (CuN), 1640 (CvN). H NMR (CF3-
COOD): d 4.40 (s, 2H, CH2), 5.15 (bs, 2H, NH2), 7.77 (m,
5H, phenyl), 9.07 (s, 1H, CH-pyrazole), 9.53 (s, 1H, CH-
pyrimidine).
4.1.3. General procedures for the preparation of 7-
phenyl-7H-2-substituted-mercaptopyrazolo[4,3-e]-
[1,2,4]triazolo[1,5-c] pyrimidines 6a–j. To a mixture of
compound 5 (0.228 g, 0.001 mol) and sodium acetate
(1.64 g, 0.02 mol) in ethanol (15 mL) was added the
respective halo compound (RX, 0.001 mol), then the
reaction mixture was heated under reflux for 4 h. After
cooling the solid products formed were filtered, washed with
water and recrystallized from the proper solvent.
2-(7-Phenyl-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyri-
midin-2-yl)-thioacetonitrile 6f. Using chloroacetonitrile 6f
was obtained as pale yellow crystals from ethanol. Yield
0.28 g, (91%), mp 180–182 8C. [Found: C, 54.53; H, 2.88;
N, 31.67. C14H9N7S requires: C, 54.71; H, 2.95; N, 31.90].
IR cm21 3080 (CH arom.), 2950, 2900 (CH aliph.) and 2220
(CuN). H NMR (CDCl3): d 4.05 (s, 2H, CH2), 7.48 (m,
3H, phenyl), 8.03 (m, 2H, phenyl), 8.07 (s, 1H, CH-
pyrazole), 9.07 (s, 1H, CH-pyrimidine).
1
2-(7-Phenyl-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyri-
midin-2-yl)-thioethyl acetate 6a. Using ethyl chloroacetate,
compound 6a was obtained as white crystals from ethanol.
Yield 34% (0.10 g), mp 133–135 8C. [Found: C, 54.42; H,
4.20; N, 23.50. C16H14N6SO2 requires: C, 54.22; H, 3.98; N,
23.72]. IR cm21: 3050 (CH arom.), 2950 (CH aliph.), 1750
(CvO); 1H NMR (CDCl3): d 1.30 (t, 3H, CH2CH3,
J¼7.3 Hz), 4.07 (s, 2H, CH2), 4.20 (q, 2H, CH2CH3,
J¼7.3 Hz), 7.43 (m, 3H, phenyl), 8.03 (m, 2H, phenyl), 8.37
(s, 1H, CH-pyrazole), 8.93 (s, 1H, CH-pyrimidine). MS: m/z
355.19 (Mþ).
2-Methylthio-7-phenyl-7H-pyrazolo[4,3-e][1,2,4]tria-
zolo[1,5-c]pyrimidine 6g. Using methyl iodide 6g was
obtained as white platelets from ethanol. Yield 0.27 g,
(95%), mp 208–210 8C. [Found: C, 55.16; H, 3.46; N,
29.59. C13H10N6S requires: C, 55.30; H, 3.57; N, 29.70]. IR
cm21 3050 (CH arom.), 2980 (CH aliph.), 1640 (CvN). 1H
NMR (CDCl3): d 2.73 (s, 3H, CH3), 7.47 (m, 3H, phenyl),
8.17 (m, 2H, phenyl), 8.43 (s, 1H, CH-pyrazole), 8.83 (s,
1H, CH-pyrimidine).
2-Ethylthio-7-phenyl-7H-pyrazolo[4,3-e][1,2,4]tria-
zolo[1,5-c]pyrimidine 6h. Using ethyl iodide 6h was
obtained as white crystals from ethanol. Yield 0.14 g,
(48%), mp 168–170 8C. [Found: C, 56.60; H, 4.18; N,
28.14. C14H12N6S requires: C, 56.74; H, 4.08; N, 28.36]. IR
cm21 3050 (CH arom.), 2950 (CH aliph.), 1640 (CvN). 1H
NMR (CDCl3): d 1.5 (t, 3H, CH3, J¼7.2 Hz), 3.30 (q, 2H,
CH2, J¼7.2 Hz), 7.43 (m, 3H, phenyl), 8.03 (m, 2H,
phenyl), 8.40 (s, 1H, CH-pyrazole), 8.98 (s, 1H, CH-
pyrimidine).
2-(7-Phenyl-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyri-
midin-2-yl)-thioacetic acid 6b. Using chloroacetic acid 6b
was obtained as yellow crystals from ethanol–dioxane
(1:1). Yield 0.26 g, (80%), mp 295–297 8C. [Found: C,
51.44; H, 2.98; N, 25.56. C14H10N6SO2 requires: C, 51.52;
H, 3.08; N, 25.76]. IR cm21 3050 (CH arom.), 2900–2820
(CH aliph.), 3100–2400 (OH), 1700 (CvO), 1640 (CvN).
1H NMR (DMSO-d6): d 4.13 (s, 2H, CH2), 5.07 (m, 1H,
OH), 7.57 (m, 3H, phenyl), 8.10 (m, 2H, phenyl), 8.70 (s,
1H, CH-pyrazole), 9.57 (s, 1H, CH-pyrimidine).
N-(p-Tolyl)-2-(7-phenyl-7H-pyrazolo[4,3-e][1,2,4]tri-
azolo[1,5-c]pyrimidin-2-yl)-thioacetamide 6i. Using
2-chloro-N-(p-tolyl)-acetamide 6i was obtained as yellow
crystals from ethanol. Yield 0.13 g, (56%), mp 183–185 8C.
[Found: C, 60.62; H, 3.98; N, 23.42. C21H17N7SO requires:
C, 60.70; H, 4.12; N, 23.60]. IR cm21 3300 (NH), 3030 (CH
arom.), 2900 (CH aliph.), 1650 (CvO). 1H NMR (DMSO-
d6): d 2.33 (s, 3H, CH3), 4.37 (s, 2H, CH2), 7.03 (m, 2H,
phenyl), 7.47 (m, 5H, phenyl), 8.10 (m, 2H, phenyl), 8.60 (s,
1H, CH-pyrazole), 8.77 (s, 1H, CH-pyrimidine), 10.57 (s,
1H, NH).
Ethyl-2-(7-phenyl-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-
c]pyrimidin-2-yl)-thio formate 6c. Using ethylchloro-
formate 6c was obtained as yellow crystals from benzene.
Yield 0.163 g, (48%), mp 295–297 8C. [Found: C, 52.75; H,
3.70; N, 24.46. C15H12N6SO2 requires: C, 52.93; H, 3.55; N,
24.69]. IR cm21 3080 (CH arom.), 1730 (CvO), 1640
(CvN). 1H NMR (CDCl3): d 1.37 (t, 3H, CH2CH3,
J¼7.2 Hz), 4.37 (q, 2H, CH2CH3, J¼7.2 Hz), 7.47 (m,
3H, phenyl), 8.13 (m, 2H, phenyl), 8.53 (s, 1H, CH-
pyrazole), 9.20 (s, 1H, CH-pyrimidine).
1-(7-Phenyl-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyri-
midin-2-yl)-thiopropanone 6d. Using chloroacetone 6d was
obtained as buff crystals from ethanol. Yield 0.131 g, (42%),
mp 188–189 8C. [Found: C, 53.70; H, 3.61; N, 26.80.
C14H12N6SO requires: C, 53.83; H, 3.87; N, 26.91]. IR
(7-Phenyl-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimi-
din-2-ylthio) malononitrile 6j. Using bromomalononitrile 6j
was obtained as buff crystals from ethanol–dioxane (1:1).
Yield 0.122 g, (36.7%), mp 205–207 8C. [Found: C, 53.99;
H, 2.60; N, 33.84. C15H8N8S requires: C, 54.21; H, 2.43; N,
33.72]. IR cm21 3080 (CH arom.), 2900 (CH aliph.), 2200
(CuN), 1640 (CvN). 1H NMR (DMSO-d6): d 7.51 (m, 4H,
phenyl and CH(CN)2), 8.01 (m, 2H, phenyl), 8.60 (s, 1H,
CH-pyrazole), 9.03 (s, 1H, CH-pyrimidine).
1
cm21 3050 (CH arom.), 1700 (CvO), 1640 (CvN). H
NMR (CDCl3): d 2.37 (s, 3H, CH3), 4.13 (s, 2H, CH2), 7.43
(m, 3H, phenyl), 8.13 (m, 2H, phenyl), 8.43 (s, 1H, CH-
pyrazole), 9.00 (s, 1H, CH-pyrimidine).

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P. G. Baraldi et al. / Tetrahedron 60 (2004) 5093–5104
4.1.4. General procedure for the preparation of 3-
substituted-7-phenyl-7H-2,3-dihydro-2-thioxo-pyra-
C, 56.68; H, 3.96; N, 33.06]. IR cm21 3200 (NH), 3020
(CH-arom.), 1630 (CvN), 1660 (CvO). 1H NMR (CDCl3):
d 7.55 (m, 3H, phenyl), 8.11 (m, 2H, phenyl), 8.33 (s, 1H,
CHO), 8.36 (s, H, CH-pyrazole), 8.40 (s, 1H, CH-
pyrimidine), 10.24 (m, 2H, 2NH). MS: m/z 254.25 (Mþ).
zolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines 7a–c.
A
mixture of 5 (0.268 g, 0.001 mol), 36% aqueous formal-
dehyde (1 mL), methanol (20 mL) and selected amines
(0.001 mol) was stirred at room temperature for about 3 h.
The solid products formed were filtered off and recrystal-
lized from the proper solvent.
4.1.7. 2-Methyl-7-phenyl-7H-pyrazolo[4,3-e][1,2,4]tri-
azolo[1,5-c]pyrimidine 9. A mixture of 4a (0.226 g,
0.001 mol) and acetic acid (15 mL) was refluxed for 5 h.
After cooling and dilution with ice/water (20 mL), the white
precipitate formed was filtered off and recrystallized from
ethanol to give white crystals. Yield 0.16 g, (64%), mp
185–187 8C. [Found: C, 62.53; H, 4.29 N, 33.35. C13H10N6
requires: C, 62.39; H, 4.03; N, 33.58]. IR cm21 3050 (CH-
arom.), 1640 (CvN).1H NMR (CDCl3): d 2.65 (s, 3H,
CH3), 7.46 (m, 3H, phenyl), 8.13 (m, 2H, phenyl), 8.48 (s,
1H, CH-pyrazole), 9.06 (s, 1H, CH-pyrimidine). MS: m/z
250 (Mþ).
3-(Morpholin-4-yl-methyl)-7-phenyl-7H-2,3-dihydro-2-
thioxopyrazolo[4,3-e][1,2,4] triazolo[1,5-c]pyrimidine 7a.
Using morpholine 7a was obtained as white crystals
(methanol). Yield 0.174 g, (48%), mp 152–154 8C.
[Found: C, 55.40; H, 4.42; N, 26.71. C17H17N7SO requires:
C, 55.57; H, 4.66; N, 26.68]. IR cm21 2900, 2800 (CH
1
aliph.), 1640 (CvN), 1150 (CvS). H NMR (CDCl3): d
2.67 (t, 4H, NCH2, J¼3.2 Hz), 3.67 (t, 4H, OCH2,
J¼3.2 Hz), 5.03 (s, 2H, CH2), 7.40 (m, 3H, Phenyl), 7.98
(m, 2H, Phenyl), 8.40 (s, 1H, CH-pyrazole), 8.93 (s, 1H,
CH-pyrimidine).
4.1.8. N-(4-Imino-1-phenyl-1H-4,5-dihydropyrazolo[3,
4-d]pyrimidin-5-yl)benzamide 10. To a stirred solution
of 4a (0.452 g, 0.002 mol) in pyridine (5 mL), benzoyl
chloride (0.28 g, 0.002 mol) was added dropwise and
stirring was continued for 6 h. After dilution with ice/
water mixture (35 mL) the solid product formed was
collected by filtration and recrystallized from ethanol to
furnish white crystals. Yield 0.52 g, (79%), mp 265–
267 8C. [Found: C, 65.27; H, 4.42 N, 25.32. C18H14N6O
requires: C, 65.44; H, 4.27; N, 25.44]. IR cm21 3230 (NH),
3-(Benzylaminomethyl)-7-phenyl-7H-2,3-dihydro-2-thioxo-
pyrazolo[4,3-e][1,2,4] triazolo[1,5-c]pyrimidine 7b. Using
benzylamine 7b was obtained as white crystals (ethanol–
dioxane 2:1). Yield 0.17 g, (44%), mp 218–220 8C. [Found:
C, 61.70; H, 4.25; N, 25.54. C20H17N7S requires: C, 61.99;
H, 4.42; N, 25.31]. IR cm21 3100 (NH), 3050 (CH arom.),
1
2980 (CH aliph.), 1640 (CvN), 1210 (CvS). H NMR
(CF3COOD): d 5.00 (s, 2H, CH2), 6.30 (s, 2H, CH2), 7.66
(m, 10H, phenyl), 8.93 (s, 1H, CH-pyrazole), 9.43 (s, 1H,
CH-pyrimidine).
1
3050 (CH-arom.), 1700 (CvO), 1630 (CvN). H NMR
(DMSO-d6): d 7.51 (m, 6H, phenyl), 8.06 (m, 4H, phenyl),
8.26 (s, 1H, CH-pyrazole), 8.50 (s, 1H, CH-pyrimidine), 10.33
(s, 1H, NH), 10.83 (bs, 1H, NHCO). MS: m/z 330.95 (Mþ).
3-(Phenylaminomethyl)-7-phenyl-7H-2,3-dihydro-2-thioxo-
pyrazolo[4,3-e][1,2,4] triazolo[1,5-c]pyrimidine 7c. Using
aniline 7c was obtained as white crystals (ethanol–dioxane;
1:1). Yield 0.15 g, (40%), mp 170–173 8C. [Found: C,
61.31; H, 4.20; N, 26.39. C19H15N7S requires: C, 61.11; H,
4.05; N, 26.26]. IR cm21 3100 (NH), 3030 (CH arom.),
4.1.9. 2,7-Diphenyl-7H-pyrazolo[4,3-e][1,2,4]tri-
azolo[1,5-c]pyrimidine 11. A solution of 10 (0.20 g,
0.64 mmol) in POCl3 was heated under reflux for 8 h.
After cooling, the reaction mixture was poured into ice/
water mixture (35 mL) and neutralized with ammonium
hydroxide solution. The solid product formed was filtered
off and recrystallized from ethanol to give buff crystals.
Yield 0.18 g, (57%), mp 178–180 8C. [Found: C, 69.50; H,
3.77: N, 26.74. C18H12N6 requires: C, 69.22; H, 3.87; N,
26.91]. IR cm21 3230 (NH), 3050 (CH-arom.), 1700
1
2900 (CH aliph.), 1640 (CvN), 1230 (CvS). H NMR
(CF3COOD): d 4.03 (s, 2H, CH2), 7.70 (m, 10H, Phenyl),
8.93 (s, 1H, CH-pyrazole), 9.46 (s, 1H, CH-pyrimidine).
4.1.5. 7-Phenyl-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]-
pyrimidine 8. A mixture of 4a (0.226 g, 0.001 mol) and
triethylorthoformate (5 mL) in dimethylformamide (5 mL)
was refluxed for 1 h. After cooling and dilution with ice/
water (30 mL), the solid product formed was filtered off and
recrystallized from ethanol to furnish 8 as gray crystals.
Yield 0.123 g, (52%), mp 178–180 8C. [Found: C, 61.25; H,
3.56; N, 35.31. C12H8N6 requires: C, 61.01; H, 3.41; N,
35.58]. IR cm21 3050 (CH-arom.), 1630 (CvN).1H NMR
(CDCl3): d 7.46 (m, 3H, phenyl), 8.65 (m, 2H, phenyl), 8.36
(s, 1H, CH-pyrazole), 8.50 (s, 1H, CH-pyrimidine), 9.17 (s,
1H, CH-triazole). MS: m/z 236.2 (Mþ).
1
(CvO), 1630 (CvN). H NMR (DMSO-d6): d 7.50 (m,
6H, phenyl), 8.04 (m, 4H, phenyl), 8.36 (s, 1H, CH-
pyrazole), 8.47 (s, 1H, CH-pyrimidine). MS: m/z 312.32
(Mþ).
4.1.10. 4-(Acetyl-imino)-5-diacetylamino-1-phenyl-1H-
pyrazolo[3,4-d]pyrimidine 12.
A suspension of 4a
(0.45 g, 0.002 mol) in acetic anhydride (10 mL) was heated
under reflux for 1 h. After cooling, the solvent was
concentrated under reduced pressure, then the reaction
mixture was poured into ice-water (40 mL) to give a solid
precipitate which was filtered off and recrystallized from
petroleum ether 60/80 to furnish 12 as buff crystals. Yield
0.36 g, (51%), mp 112–115 8C. [Found: C, 57.76; H, 4.62;
N, 23.76. C17H16N6O3 requires C, 57.95; H, 4.58; N, 23.85].
IR cm21 3100 (CH arom.), 2910 (CH aliph.), 1718 (CvO).
1H NMR (CDCl3): d 2.43 (s, 6H, 2CH3), 2.50 (s, 3H, CH3),
7.52 (m, 3H, phenyl), 8.06 (m, 2H, phenyl), 8.23 (s, 1H, CH-
pyrazole), 8.72 (s, 1H, CH-pyrimidine). MS: m/z 352 (Mþ).
4.1.6. 5-Formylamino-4-imino-1-pheny-1H-4,5-dihydro-
pyrazolo[3,4-d]pyrimidine 8a. A mixture of 4a (0.226 g,
0.001 mol) and ethyl formate (5 mL) in dimethylformamide
(5 mL) was heated under reflux for about 5 h. After cooling,
the solid product formed was collected, washed with water
(30 mL) and recrystallized from ethanol to afford 8a as
white crystals. Yield 0.16 g, (63%), mp 271–273 8C.
[Found: C, 56.83; H, 3.92 N, 32.98. C12H10N6O requires:

P. G. Baraldi et al. / Tetrahedron 60 (2004) 5093–5104
5101
4.1.11. 2-Phenylamino-7-phenyl-7H-pyrazolo[4,3-e]-
[1,2,4]triazolo[1,5-c]pyrimidine 14. A suspension of 4a
(0.226 g, 0.001 mol) and phenylisothiocyanate (0.135 g,
0.001 mol) in pyridine (10 mL) was heated under reflux for
5 h. After cooling the reaction mixture was poured into ice/
water (30 mL) and neutralized with diluted 10% HCl to give
a buff solid precipitate. This product was collected and
crystallized from ethanol–DMF (3:1) to furnish 14 as a buff
powder. Yield 0.24 g, (73.4%), mp 274–276 8C. [Found: C,
65.94; H, 3.86; N, 29.76. C18H13N7 requires C, 66.04; H,
4.00; N, 29.95]. IR cm21 3100 (NH), 3050 (CH arom.),
1650 (CvN). 1H NMR (DMSO-d6): d 7.50 (m, 8H, phenyl),
8.04 (m, 2H, phenyl), 8.22 (s, 1H, NH), 8.63 (s, 1H, CH-
pyrazole), 9.03 (s, 1H, CH-pyrimidine). MS: m/z 371.94
(Mþ).
yellow crystals, mp .300 8C. [Found: C, 43.92; H, 2.51; N,
38.65. C8H6N6O2 requires: C, 44.04; H, 2.77; N, 38.52]. IR
1
cm21 3340 (NH), 1700 (CvO), 1660 (CvO). H NMR
(DMSO-d6): d 3.40 (s, 3H, CH3), 8.20 (s, 1H, CH-pyrazole),
8.45 (s, 1H, CH-pyrimidine), 9.30 (bs, 1H, NH). MS: m/z
219.3 (Mþ).
4.1.14. Ethyl N-(4-imino-1-phenyl-1H-4,5-dihydropyra-
zolo[3,4-d]pyrimidin-5-yl)-carbamoyl formate 18.
A
mixture of 4a (0.226 g, 0.001 mol) and diethyl oxalate
(5 mL) was warmed with stirring at 40 8C for 30 min. The
solid precipitate formed was collected and recrystallized
from dioxane to furnish 18 as buff crystals. Yield 0.25 g,
(77%), mp 298–300 8C. [Found: C, 55.41; H, 4.56 N, 25.46.
C15H14N6O3 requires C, 55.21; H, 4.32; N, 25.76]. IR cm21
3200 (NH), 3050 (CH arom.), 1710 (CvO), 1670 (CvO)
1
4.1.12. N-(4-Imino-1-phenyl-1H-4,5-dihydropyra-
zolo[3,4-d]pyrimidin-3-yl)-2-chloro acetamide 15.
and 1630 (CvN). H NMR (DMSO-d6): d 1.33 (t, 3H,
A
CH2CH3, J¼7.3 Hz), 4.30 (q, 2H, CH2H3, J¼7.3 Hz), 7.40
(m, 3H, phenyl), 8.08 (m, 2H, phenyl), 8.23 (s, 1H, CH-
pyrazole), 8.37 (s, 1H, CH-pyrimidine), 8.88 (s, 2H, 2NH).
MS: m/z 326 (Mþ).
mixture of 4a (0.226 g, 0.002 mol) and chloroacetyl
chloride (0.112 g, 0.001 mol) in dioxane (10 mL) was
refluxed for 6 h. The white precipitate formed was collected
and recrystallized from ethanol to give fluffy white crystals.
Yield 0.22 g, (74%), mp 205–208 8C. [Found: C, 55.52; H,
3.77; N, 27.55. C13H11ClN6O requires C, 55.86; H, 3.66; N,
27.76]. IR cm21 3150 (NH), 2980, 2780 (CH-aliph.), 1710
(CvO), 1630 (CvN). 1H NMR (DMSO-d6): d 4.50 (s, 2H,
CH2), 7.58 (m, 3H, phenyl), 8.12 (m, 2H, phenyl), 8.45 (s,
1H, CH-pyrazole), 8.80 (s, 1H, CH-pyrimidine), 8.91–9.1
(bs, 2H, 2NH). MS: m/z 302.76 (Mþ).
4.1.15. Ethyl (1-phenyl-1H-pyrazolo[4,3-e][1,2,4]tri-
azolo[1,5-c]pyrimidin-5-yl) carboxylate 19. A mixture of
4a (0.226 g, 0.001 mol) and diethyl oxalate (5 mL) was
refluxed for 8 h. The reaction mixture was then concentrated
at reduced pressure and left to cool. The solid product
formed was filtered off and recrystallized from ethanol to
furnish 19 as buff crystals. Yield 0.27 g, (88%), mp 212–
214 8C. [Found: C, 58.34; H, 3.96 N, 26.99. C15H12N6O2
requires: C, 58.43; H, 3.92; N, 27.26]. IR cm21 3050
(CH-arom.), 1730 (CvO). 1650 (CvN).1H NMR (CDCl3):
d 1.52 (t, 3H, CH2CH3, J¼7.4 Hz), 4.55 (q, 2H, CH2H3,
J¼7.4 Hz), 7.46 (m, 3H, phenyl), 8.06 (m, 2H, phenyl), 8.53
(s, 1H, CH-pyrazole), 9.23 (s, 1H, CH-pyrimidine).
4.1.13. General procedure for the synthesis of 1(2)-
substituted-1(2)H,7H-5,6-dioxo-5,6-dihydropyra-
zolo[30,40:4,5]pyrimido[1,6-b] [1,2,4]triazine 17a–c. To a
solution of 4a–c (0.001 mol) in dry benzene (10 mL),
oxalyl chloride (0.126 g, 0.001 mol) was added. The
reaction mixture was heated under reflux for 8 h. The solids
formed were collected by filtration and recrystallized from a
mixture of ethanol/benzene (1:1) to afford 17a–c as yellow
crystals
4.1.16. General procedure for the preparation of 7(8)-
substituted-7(8)H-2-oxo-2,3-dihydropyrazolo[4,3-e]-
[1,2,4]triazolo[1,5-c]pyrimidines 21a–c. A mixture of
4a–c (0.001 mol) and ethyl chloroformate (0.001 mol) in
dry benzene (10 mL) was heated under reflux for 8 h. After
cooling and triturating with ethanol the solid formed was
filtered off and recrystallized from dioxane/ethanol (1:2) to
furnish compounds 21a–c as crystals.
1-Phenyl-1H,7H-5,6-dioxo-5,6-dihydropyrazolo[30,40:4,
5]pyrimido[1,6-b] [1,2,4]triazine 17a. Yield 0.23 g, (78%),
yellow crystals, mp .300 8C. [Found: C, 55.60; H, 2.68;
N, 29.79. C13H8N6O2 requires: C, 55.71; H, 2.88; N,
29.99]. IR cm21 3200 (NH), 3080 (CH arom.), 2900 (CH
1
aliph.), 1730 (CvO), 1710 (CvO). H NMR (DMSO-d6):
7-Phenyl-7H-2-oxo-2,3-dihydropyrazolo[4,3-e][1,2,4]tri-
azolo[1,5-c]pyrimidine 21a. Yield 0.13 g (47%), buff
crystals, mp 258–260 8C. [Found: C, 57.30; H, 2.98; N,
33.18. C12H8N6O requires: C, 57.14; H, 3.19; N, 33.32]. IR
d 7.48 (m, 5H, arom.); 7.98 (s, 1H, CH-pyrazole), 8.23 (s,
1H, CH-pyrimidine), 10.82 (bs, 1H, NH). MS: m/z 280
(Mþ).
1
cm21 3300 (NH), 1680 (CvO), 1640 (CvN). H NMR
1-(2-Phenylethyl)-1H,7H-5,6-dioxo-5,6-dihydropyra-
zolo[30,40:4,5]pyrimido[1,6-b] [1,2,4]triazine 17b. Yield
0.135 g (50.52%), yellow crystals, mp .300 8C. [Found C,
58.22; H, 3.81; N, 27.02. C15H12N6O2 requires: C, 58.44; H,
3.92; N, 27.26]. IR cm21 3400 (NH), 2920 (CH arom.),
(DMSO-d6): d 7.44 (m, 3H, phenyl), 7.98 (m, 2H, phenyl),
8.40 (s, 1H, CH-pyrazole), 8.63 (s, 1H, CH-pyrimidine),
10.52 (bs, 1H, NH). MS: m/z 252.23 (Mþ).
7-(2-phenylethyl)-7H-2-oxo-2,3-dihydropyrazolo[4,3-e]-
[1,2,4]triazolo[1,5-c]pyrimidine 21b. Yield 0.10 g (20%),
buff crystals, mp 290 8C. [Found: C, 59.71; H, 4.26; N,
29.95. C14H12N6O requires: C, 59.99; H, 4.32; N, 29.98]. IR
cm21 3440 (NH), 3090 (CH arom.), 1685 (CvO). 1H NMR
(DMSO-d6): d 3.21 (t, 2H, CH2, J¼7.2 Hz), 4.60 (t, 2H,
CH2, J¼7.2 Hz), 7.23 (m, 5H, arom.), 7.88 (s, 1H, CH-
pyrazole), 8.11 (s, 1H, CH-pyrimidine), 11.41 (bs, 1H, NH).
MS: m/z 281.32 (Mþ).
1
2650 (CH aliph.), 1740 (CvO), 1700 (CvO). H NMR
(DMSO-d6): d 3.23 (t, 2H, CH2, J¼7.2 Hz), 4.67 (t, 2H,
CH2, J¼7.2 Hz), 7.24 (m, 5H, arom.), 8.09 (s, 1H, CH-
pyrazole), 8.35 (s, 1H, CH-pyrimidine), 9.32 (bs, 1H, NH).
MS: m/z 309.2 (Mþ).
2-Methyl-2H,7H-5,6-dioxo-5,6-dihydropyrazolo[30,40:4,
5]pyrimido[1,6-b] [1,2,4]triazine 17c. Yield 0.166 g (56%),

5102
P. G. Baraldi et al. / Tetrahedron 60 (2004) 5093–5104
8-Methyl-8H-2-oxo-2,3-dihydropyrazolo[4,3-e][1,2,4]tri-
azolo[1,5-c]pyrimidine 21c. Yield 60 mg (23%), buff
crystals, mp .300 8C. [Found: C, 44.35; H, 3.02; N, 44.08.
C7H6N6Orequires:C,44.21;H, 3.18;N,44.19]. IRcm21 3450
(NH), 3180 (CH aliph.), 1690 (CvO). 1H NMR (DMSO-d6):
d 3.73 (s, 3H, CH3), 7.43 (s, 1H, CH-pyrazole), 8.01 (s, 1H,
CH-pyrimidine), 11.79 (bs, 1H, NH). MS: m/z 191.16 (Mþ).
C, 56.75; H, 4.08; N, 28.37]. IR cm21 3150 (NH), 2600–
2400 (OH), 1695 (CvO), 1600 (CvN). 1H NMR (DMSO-
d6): d 2.21 (s, 3H, CH3), 7.47 (m, 3H, phenyl), 8.20 (m, 2H,
phenyl), 8.57 (s, 1H, CH-pyrazole), 8.80 (s, 1H, CH-
pyrimidine), 9.12 (bs, 1H, NH), 11.20 (bs, 1H, OH). MS:
m/z 296.87 (Mþ).
4.1.21. 6-Methyl-1-phenyl-1H-5-oxo-pyrazolo[30,40:4,5]-
pyrimido[1,6-b]-1,2,4-]triazine 26. A solution of 25
(0.18 g, 0.0006 mol) and POCl3 (10 mL) was heated under
reflux for 1 h. After cooling, the reaction mixture was
poured into ice-water (50 mL) and neutralized with
ammonia solution to give dark buff precipitate. The solid
was filtered off and recrystallized from ethanol to afford 26
as buff crystals. Yield 0.124 g (73.4%), mp 294–296 8C.
[Found: C, 60.88; H, 3.98; N, 28.30. C14H10N6O requires:
C, 60.42; H, 4.08; N, 28.37]. IR cm21 3050 (CH arom.),
4.1.17. 5-(N,N-Diethoxycarbonylamino)-4-imino-1-
phenyl-1H-pyrazolo[3,4-d]pyrimidine 22. A mixture of
4a (0.226 g, 0.001 mol) and ethyl chloroformate (0.162 g,
0.0015 mol) in dry benzene (10 mL) was heated under
reflux for 8 h. The reaction mixture was concentrated to
one-third its volume and triturated with ethanol to give buff
solid product which was filtered off and recrystallized from
petroleum ether 60/80 to furnish 22 as buff crystals. Yield
0.14 g (38%), mp 118–120 8C. [Found: C, 55.30; H, 4.79:
N, 22.45. C17H18N6O4 requires: C, 55.13; H, 4.90; N,
22.69]. IR cm21 3290 (NH), 3050 (CH-arom.), 3980, 3910
(CH-aliph.), 1740 (CvO), 1630 (CvN). 1H NMR (DMSO-
d6): d 1.30 (m, 6H, 2CH2CH3), 4.26 (m, 4H, 2CH2CH3),
7.36 (m, 3H, phenyl), 8.06 (m, 2H, phenyl), 8.37 (s, 1H, CH-
pyrazole), 8.73 (s, 1H, CH-pyrimidine), 8.92 (bs, 1H, NH).
MS: m/z 370.1 (Mþ).
1
2900 (CH aliph.), 1640 (CvO). H NMR (CF3COOD): d
2.73 (s, 3H, CH3), 7.70 (m, 3H, phenyl), 7.90 (m, 2H,
phenyl), 9.13 (s, 1H, CH-pyrazole), 9.23 (s, 1H, CH-
pyrimidine). MS: m/z 278.20 (Mþ).
4.1.22. General procedure for the preparation of 5,7-
dimethyl-1(2)-substituted-1(2)H-pyrazolo[40,30:4,5]-
pyrimido[1,6-b][1,2,4]triazepines 27a–c. A mixture of
4a–c (0.001 mol) and acetylacetone (0.01 mol) in ethanol
(15 mL) was heated under reflux for 1 h. After cooling, the
solid formed was collected and crystallized from ethanol to
afford 27a–c as crystals.
4.1.18. Ethyl (1-phenyl-1H-pyrazolo[4,3-e][1,2,4]tri-
azolo[1,5-c]pyrimidin-5-yl)acetate 23. A suspension of
4a (0.226 g, 0.001 mol) and diethyl malonate (5 mL) was
heated under reflux over its boiling point for 10 h. The
yellow solid product formed was filtered off and crystallized
from dioxane into yellow crystals. Yield 0.14 g, (42%), mp
.300 8C. [Found: C, 59.48; H, 4.50: N, 25.99. C16H14N6O2
requires: C, 59.62; H, 4.38; N, 26.08]. IR cm21 3050 (CH
arom.), 2950, 2800 (CH aliph.), 1730 (CvO), 1630 (CvN).
1H NMR (DMSO-d6): d 1.23 (t, 3H, CH2CH3), 4.11 (q, 2H,
CH2CH3), 5.15 (s, 2H, CH2), 7.46 (m, 3H, phenyl), 8.13 (m,
2H, phenyl), 8.40 (s, 1H, CH-pyrazole), 8.70 (s, 1H, CH-
pyrimidine). MS: m/z 322.32 (Mþ).
5,7-Dimethyl-1-phenyl-1H-pyrazolo[40,30:4,5]pyrimido-
[1,6-b][1,2,4]triazepine 27a. Yield 0.112 g, (38%), white
crystals, mp 152–153 8C. [Found: C, 65.95; H, 4.70; N,
28.68. C16H14N6 requires: C, 66.19; H, 4.86; N, 28.95]. IR
cm21 3050 (CH arom.), 2900 (CH aliph.), 1565 (CvN). 1H
NMR (CDCl3): d 2.37 (s, 3H, CH3), 2.80 (s, 3H, CH3), 6.03
(s, 1H, CH-triazepine), 7.34 (m, 3H, phenyl), 8.15 (m, 2H,
phenyl), 8.73 (s, 1H, CH-pyrazole), 8.82 (s, 1H, CH-
pyrimidine). MS: m/z 290 (Mþ).
4.1.19. 7-Phenyl-7H-pyrazolo[4,3-e]-1,2,3,4-tetra-
zolo[1,5-c]pyrimidine 24. To a cold solution of 4a
(0.226 g, 0.001 mol) in acetic acid (10 mL) was added an
ice-cold solution of sodium nitrite (0.21 g/5 mL H2O,
0.003 mol) with stirring during five minutes. Stirring was
then continued for 2 h. The reaction mixture was poured
into water (60 mL) and the solid formed was filtered off and
recrystallized from ethanol to afford 24 as buff crystals.
Yield 0.20 g, (84%), mp 200–202 8C. [Found: C, 55.47; H,
2.89; N, 41.29. C11H7N7 requires: C, 55.69; H, 2.97; N,
41.34]. IR cm21 3060 (CH arom.), 2910 (CH aliph.), 1640
(CvN). 1H NMR (DMSO-d6): d 7.56 (m, 3H, phenyl), 8.01
(m, 2H, phenyl), 8.90 (s, 1H, CH-pyrazole), 10.16 (s, 1H,
CH-pyrimidine). MS: m/z 237.22 (Mþ).
5,7-Dimethyl-1-(2-phenylethyl)-1H-pyrazolo[40,30:4,5]-
pyrimido[1,6-b][1,2,4]triazepine 27b. Yield 85 mg (27%),
white crystals, mp 210 8C. [Found: C, 67.72; H, 5.36; N,
26.66. C18H18N6 requires: C, 67.90; H, 5.70; N, 26.40]. IR
cm21 3250 (CH arom.), 2940 (CH aliph.), 1580 (CvN). 1H
NMR (CDCl3): d 2.36 (s, 3H, CH3), 2.79 (s, 3H, CH3), 3.26
(t, 2H, CH2, J¼7.3 Hz), 4.73 (t, 2H, CH2, J¼7.3 Hz), 6.07
(s, 1H, CH-triazepine), 7.23 (m, 5H, arom.), 8.66 (s, 1H, CH-
pyrazole), 8.68 (s, 1H, CH-pyrimidine). MS: m/z 319.2 (Mþ).
2,5,7-Trimethyl-2H-pyrazolo[40,30:4,5]pyrimido[1,6-b]-
[1,2,4]triazepine 27c. Yield 90 mg (32%), white crystals,
mp 255 8C. [Found: C, 57.97; H, 5.11; N, 36.97. C11H12N6
requires: C, 57.88; H, 5.30; N, 36.82]. IR cm21 3000 (CH
1
4.1.20. 2-(4-Imino-1-phenyl-1H-4,5-dihydropyra-
zolo[3,4-d]pyrimidin-5-ylimino) propionic acid 25. A
solution of 4a (0.45 g, 0.002 mol) and pyruvic acid
(0.208 g, 0.002 mol) in ethanol (15 mL) was heated under
reflux for 5 h. After cooling, the reaction mixture was
poured into water (60 mL). The solid precipitate formed was
filtered off and recrystallized from ethanol–dioxane (1:1) to
give buff crystals. Yield 0.38 g, (64.4%), mp 258–260 8C.
[Found: C, 56.78; H, 3.96; N, 28.30. C14H12N6O2 requires:
aliph.), 1610 (CvN). H NMR (DMSO-d6): d 2.41 (s, 3H,
CH3), 2.82 (s, 3H, CH3), 3.32 (s, 3H, N–CH3), 6.21 (s, 1H,
CH-triazepine), 8.38 (s, 1H, CH-pyrazole), 8.51 (s, 1H, CH-
pyrimidine). MS: m/z 228.3 (Mþ).
4.1.23. 3-(4-Imino-1-phenyl-1H-1,4-dihydropyra-
zolo[3,4-d]pyrimidin-5-yl-imino)-1-phenylbutan-1-one
28. A mixture of 4a (0.226 g, 0.001 mol) and benzoyl-
acetone (0.162 g, 0.001 mol) in ethanol (20 mL) was

P. G. Baraldi et al. / Tetrahedron 60 (2004) 5093–5104
5103
refluxed for 10 h. The solvent was evaporated under reduced
pressure and the solid formed was collected and
recrystallized from ethanol to give white crystals. Yield
0.3 g, (81%), mp 150–152 8C. [Found: C, 67.95; H, 4.70; N,
22.58. C21H18N6O requires: C, 68.09; H, 4.90; N, 22.69]. IR
cm21 3400 (NH), 3030 (CH arom.), 2900 (CH aliph.), 1605
precipitate was filtered off and crystallized from ethanol to
afford 30c as white crystals. Yield 0.15 g (47%), mp 295–
297 8C. [Found: C, 56.14; H, 3.74; N, 29.98. C15H11N7O2
requires: C, 56.07; H, 3.45; N, 30.52]. IR cm21 3050 (CH
arom.), 1720 (CvO). 1H NMR (DMSO-d6): d 5.31 (bs, 2H,
NH2), 7.52 (m, 3H, phenyl), 8.09 (m, 2H, phenyl), 8.23 (s,
1H, CH-pyrazole), 8.37 (s, 1H, CH-pyrimidine), 8.50 (s, 1H,
CH-triazepine), 12.47 (bs, 1H, OH).
1
(CvO), 1585 (CvN). H NMR (CDCl3): d 2.33 (s, 3H,
CH3), 3.27 (s, 2H, CH2), 6.43 (s, 1H, NH), 7.43 (m, 8H,
Phenyl), 8.23 (m, 2H, Phenyl), 8.28 (s, 1H, CH-pyrazole),
8.63 (s, 1H, CH-pyrimidine). MS: m/z 370.2 (Mþ).
4.1.28. 1,7-Diphenyl-1H,8H-5-oxopyrazolo[30,40:4,5]-
pyrimido[1,6-b][1,2,4]triazepine 31. A suspension of 4a
(0.226 g, 0.001 mol) and ethylbenzoyl acetate (1.66 g,
0.009 mol) in ethanol (7 mL) was heated under reflux for
10 h. After concentration, the solid product formed was
filtered off and recrystallized from methanol to give 31 as
yellow crystals. Yield 0.27 g, (76%,), mp 192–94 8C.
[Found: C, 67.58; H, 4.11; N, 23.56. C20H14N6O requires:
C, 67.78; H, 3.98; N, 23.72]. IR cm21 3080 (CH arom.),
4.1.24. 1,5-Diphenyl-7-methyl-1H-pyrazolo[30,40:
4,5]pyrimido[1,6-b][1,2,4]triazepine 29. A mixture of 28
(0.19 g, 0.512 mmol) and POCl3 (15 mL) was heated under
reflux for 2 h. After cooling, the reaction mixture was
poured into a mixture of ice-cold water and neutralized with
ammonium hydroxide solution. The solid formed was
collected and recrystallized from petroleum ether (60/80)
to afford 29 as white crystals. Yield 0.12 g, (67%), mp 113–
115 8C. [Found: C, 71.38; H, 4.60; N, 23.58. C21H16N6
requires C, 71.57; H, 4.58; N, 23.85]. IR cm21 3030 (CH
1
1730 (CvO), 1640 (CvN). H NMR (CDCl3): d 5.97 (s,
1H, CH-triazepine), 7.43 (m, 6H, Phenyl), 7.83 (m, 2H,
Phenyl), 8.20 (m, 2H, Phenyl), 8.67 (s, 1H, CH-pyrazole),
8.93 (s, 1H, CH-pyrimidine), 11.06 (bs, 1H, NH). MS: m/z
354.10 (Mþ).
1
arom), 1590 (CvN). H NMR (DMSO-d6): d 2.42 (s, 3H,
CH3), 6.50 (s, 1H, CH-triazepine), 7.42 (m, 6H, Phenyl),
7.53 (m, 2H, Phenyl), 8.20 (m, 2H, Phenyl), 8.57 (s, 1H,
CH-pyrazole), 8.77 (s, 1H, CH-pyrimidine). MS: m/z 352.38
(Mþ).
4.1.29. 5-Amino-1,7-diphenyl-1H-pyrazolo[30,40:4,5]-
pyrimido[1,6-b][1,2,4]triazepine 32. A suspension of 4a
(0.45 g, 0.002 mol) and benzoylacetonitrile (0.290 g,
0.002 mol) in ethanol (20 mL) was heated under reflux for
10 h. After concentration and cooling, the solid formed was
filtered off and recrystallized from ethanol to give 32 as
scarlet red crystals. Yield 0.68 g, (97%), mp 141–143 8C.
[Found: C, 67.61; H, 4.58; N, 27.51. C20H15N7 requires C,
67.97; H, 4.28; N, 27.75]. IR cm21 3400, 3280 (NH2), 3040
(CH arom.), 1600 (CvN). 1H NMR (CDCl3): d 4.00 (s, 2H,
NH2), 5.77 (s, 1H, CH-triazepine), 7.43 (m, 5H, Phenyl),
7.83 (m, 3H, Phenyl), 8.23 (m, 2H, Phenyl), 8.70 (s, 1H,
CH-pyrazole), 9.00 (s, 1H, CH-pyrimidine). MS: m/z 353.10
(Mþ).
4.1.25. 5-Amino-1-phenyl-1H-pyrazolo[30,40:4,5]pyri-
mido[1,6-b][1,2,4]triazepine-6-carbonitrile 30a. A mix-
ture of 4a (0.226 g, 0.001 mol) and ethoxymethylene
malononitrile (0.122 g, 0.001 mol) in ethanol (10 mL) was
refluxed for 4 h. The precipitate formed after cooling was
filtered off and recrystallized from methanol to furnish 30a
as white crystals. Yield 0.18 g, (60%), mp 288–290 8C.
[Found: C, 59.31; H, 3.48; N, 36.88. C15H10N8 requires C,
59.59; H, 3.33; N, 37.07]. IR cm21 3400, 3300 (NH2), 1620
(NH2), 2220 (CuN). 1H NMR (CF3CO2D): d 5.80 (bs, 2H,
NH2), 7.70 (s, 5H, phenyl), 8.10 (s, 1H, CH-triazepine), 9.23
(s, 1H, CH-pyrazole), 9.30 (s, 1H, CH-pyrimidine). MS: m/z
302.29 (Mþ).
4.1.26. Ethyl (5-amino-1-phenyl-1H-pyrazolo[30,
40:4,5]pyrimido[1,6-b][1,2,4]triazepin-6-yl)carboxylate
30b. A mixture of compound 4a (0.226 g, 0.001 mol) and
ethyl ethoxymethylene cyanoacetate (0.16 g, 0.001 mol) in
ethanol (10 mL) was refluxed for 4 h. After cooling, the
solid precipitate was filtered off and recrystallized from
ethanol to furnish 30b as white crystals. Yield 0.28 g,
(93%), mp 215–217 8C. [Found: C, 58.67; H, 4.54; N,
28.40. C12H15N7 O2 requires C, 58.44; H, 4.33; N, 28.07].
IR cm21 3300, 3400 (NH2), 1680 (CvO). 1H NMR
(CF3CO2D): d 1.50 (t, 3H, CH2CH3, J¼7.2 Hz), 4.46 (q,
2H, CH2CH3, J¼7.2 Hz), 7.67 (s, 5H, phenyl), 8.27 (s, 1H,
CH-triazepine), 9.20 (s, 1H, CH-pyrazole), 9.30 (s, 1H, CH-
pyrimidine). MS: m/z 349.35 (Mþ).
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A
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