Convenient synthesis of new N-3-substituted pyrido[1′,2′:1,5] pyrazolo[3,4- d ]pyrimidine-2,4(1 H,3 H)-dione derivatives

Article abstract of DOI:10.1055/s-0033-1338514

Previously unknown N-3-substituted pyrido[1′,2′:1,5]pyrazolo[3, 4-d]pyrimidine derivatives were synthesized by a straightforward four-step synthesis. Starting from a 1-aminopyridinium salt, dimethyl acetylenedicarboxylate condensation followed by a fully regioselective saponification led to a pyrazolo[1,5-a]pyridine monoester as a key intermediate. A Curtius rearrangement directly followed by amine condensation afforded a urea library. A final pyrimidine ring closure resulted in achievement of the heterocyclic construction. This straightforward strategy provides an efficient method to easily access a library of rare tricyclic scaffolds and highly valuable derivatives.

Full text of DOI:10.1055/s-0033-1338514

PAPER
▌2557
paper
Convenient Synthesis of New N-3-Substituted Pyrido[1′,2′:1,5]pyrazolo[3,4-
d]pyrimidine-2,4(1H,3H)-dione Derivatives
N-3-Substituted Pyrido[1′,2′:1,5]pyrazolo[3,4-d]pyrimidine-2,4(1H,3H)-diones
Rabia Belaroussi,a,b Abderrahman El Bouakher,a,b Mathieu Marchivie,c Stéphane Massip,c Christian Jarry,c
Ahmed El Hakmaoui,a Gérald Guillaumet,*b Sylvain Routier,*b Mohamed Akssira*a
a
Équipe de Chimie Bioorganique & Analytique, URAC 22, Université Hassan II Mohammedia-Casablanca, BP 146, 28800 Mohammedia,
Morocco
Fax +212523314705; E-mail: makssira@yahoo.com
b
Institut de Chimie Organique et Analytique, Université d’Orléans, UMR CNRS 7311, 45067 Orléans Cedex, France
Fax +33(2)38494853; E-mail: gerald.guillaumet@univ-orleans.fr; E-mail: sylvain.routier@univ-orleans.fr
c
Laboratoire de Chimie Physique et Minérale, Université de Bordeaux, CNRS FRE 3396, 33000 Bordeaux, France
Received: 09.06.2013; Accepted: 04.07.2013
O
Abstract: Previously unknown N-3-substituted pyrido[1′,2′:1,5]py-
razolo[3,4-d]pyrimidine derivatives were synthesized by a straight-
forward four-step synthesis. Starting from a 1-aminopyridinium
salt, dimethyl acetylenedicarboxylate condensation followed by a
fully regioselective saponification led to a pyrazolo[1,5-a]pyridine
monoester as a key intermediate. A Curtius rearrangement directly
followed by amine condensation afforded a urea library. A final py-
rimidine ring closure resulted in achievement of the heterocyclic
construction. This straightforward strategy provides an efficient
method to easily access a library of rare tricyclic scaffolds and high-
ly valuable derivatives.
Ar
O
N
N
R
X
Y
N
N
O
S
N
H
N
H
O
OMe
II
I X = N, Y = CH or
X = CH, Y = N
O
O
NMe
N
O
S
N
Key words: pyrazolo[1,5-a]pyridines, regioselective hydrolysis,
Curtius rearrangement, pyridopyrazolo[3,4-d]pyrimidines
O
N
O
Me
III
IV
Figure 1 Some ring-fused pyrimidinediones
The preparation of pyrimidine-2,4-diones and ring-fused
derivatives continues to attract considerable attention.
Their preparation in only a few steps could lead to highly
valuable precursors and thereby also increase the molecu-
lar diversity in chemistry research programs and thus the
level of innovation. It is clear, in particular, from publica-
tions and reviews in the field that most of the pyrimidine-
dione systems are mainly associated with small classical
heterocycles, such as pyridine I or thiophene II, or in
some rare cases to more complex benzothiophene III or
benzochromene IV (Figure 1).1–5
noncommercial N-aminouracils. In this synthesis, the
preparation of amidines, as key intermediates, appears
problematic.
R1
R
O
O
N
N
O
O
N
N
NH
R2
N
N
N
In addition, interest in these series has increased in view
of the potential of N-alkylated pyrimidinedione deriva-
tives and their wide range of pharmacological activities.
Potent antiasthmatic,6 antidiabetic,7 anti-inflammatory,8
antidiuretic9 and anti-HIV10 agents are known.
VI R1, R2 = H, Me, t-Bu
V R = H, (het)aryl, alkyl
R1
R
N
N
Ph
R2
N
Our interest in rare heterocyclic structures led us to ex-
plore the synthesis, formation and functionalization of un-
N
N
N
N
N
Ph
known pyridopyrazolopyrimidinediones of type
V
VII R1 = NH2, OH
VIII R = OH, NH2, Cl, NHAr,
(Figure 2). Analysis of the literature clearly shows that
this tricyclic arrangement remains poorly described. We
consider that diones of type VI exemplify the state of the
art in the field.11 They were presented as ring-fused xan-
thines and were obtained after a three-step synthesis from
R2 = H, Me, Ph
NHCONHAr
Figure 2 Targeted structure V and some representative pyri-
do[1′,2′:1,5]pyrazolo[3,4-d]pyrimidine derivatives
Other closed structures and their access have been de-
scribed. Derivatives VII were obtained by cycloaddition
involving a preformed 1-amino-2-methylthiopyridinium
SYNTHESIS 2013, 45, 2557–2566
Advanced online publication: 25.07.2013
DOI: 10.1055/s-0033-1338514; Art ID: SS-2013-T0395-OP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

2558
R. Belaroussi et al.
PAPER
salt and acetonitriles, and then pyrimidine ring formation
under classical reactions.12 More recently, the central het-
erocyclic core of compounds VIII, which are claimed as
potent anticancer and antidiabetic drugs, was obtained by
condensation of a 1-aminopyridinium salt with malononi-
trile, followed by formation of the pyrimidine ring in a fi-
nal step.13
CO2Me
CO2Me
DMAD, K2CO3
I–
N+
N
NH2
DMF, r.t., 16 h
71%
N
1
2
NaOH, MeOH
r.t., 3 h
91%
However, interest in the previously reported methods has
decreased due to the limiting factors during synthesis such
as unsatisfactory yields or the availability of starting ma-
terial. Having in hand a versatile method leading to diones
of type V appears necessary. Here, we present an alterna-
tive method for the synthesis of novel N-3-substituted
pyrido[1′,2′:1,5]pyrazolo[3,4-d]pyrimidine-2,4(1H,3H)-
CO2Me
CO2H
N
N
3
diones V from commercially available 1-aminopyridini- Scheme 2 Synthesis of monoester 3
um iodide (1). After a multipart ‘one-pot’ reaction, includ-
ing a Curtius rearrangement, exclusive synthesis of the C-
2-aminated derivatives IX can be achieved. A final pyrim-
idine ring closure of urea derivatives leads to the N-3-sub-
stituted derivatives V (Scheme 1).
CO2Me
pyrimidine
formation
I–
3 steps
Curtius
NHR
V
N+
N
NH2
urea ring
closure
N
1
IX
Scheme 1 Envisioned synthesis
It is well known that the amino group of salt 1 is able to
react with electrophiles such as nitriles, ketones and elec-
tro-deficient carbons of alkynes or alkenes.14 In addition,
the described condensation of dimethyl acetylenedicar-
boxylate (DMAD) with aminopyridinium salt 1 leading to
diester 215 appears to be uncertain; nevertheless, we per-
formed an optimization of the reaction in anhydrous N,N-
dimethylformamide. We fortunately found that the use of
only 1.5 equivalents of DMAD and 1.4 equivalents of
base gave, after flash chromatography, a satisfying 71%
yield of diester 2 in a reproducible manner (Scheme 2). To
pursue our objective, the next step required selective
saponification16 which occurred with a stoichiometric
amount of sodium hydroxide in methanol and furnished
the previously unknown monoester 3 in a 91% yield.
Figure 3 Single-crystal X-ray analysis of monoester 317
Treatment of acid 3 with an excess of ethyl chloroformate
in anhydrous tetrahydrofuran in the presence of triethyl-
amine at low temperature led to the mixed anhydride
which was readily transformed, after completion of the
prime reaction, into azide 4 by the addition of sodium
azide (1.7 equiv) in the presence of a small amount of
water at room temperature (Scheme 3). The Curtius rear-
rangement was next carried out on the crude azide 4 in
boiling toluene and the unisolated isocyanate intermediate
was quenched at room temperature with various amines to
afford compounds 5–14 of type IX in good yields.
The selectivity of the reaction was proved by the X-ray
analysis of a single crystal of the monoester 3. As depicted
in the ORTEP representation (Figure 3), the pyrazolo[1,5-
a]pyridine is substituted by a carboxy group at C-2 and by
a methoxycarbonyl group at C-3. The rather planar struc-
ture is due to the formation of an intramolecular interac-
tion between the acidic proton and one of the oxygen
atoms of the C-3 ester group.
The first nucleophilic condensations onto the isocyanate
were realized by the direct addition of amines, but only
low yields of ureas were obtained. A cautious evaporation
of the volatiles to dryness and dissolution of the crude ma-
terial in dichloromethane gave the desired ureas 5–14
which were obtained on a gram scale using only a stoi-
chiometric amount of amine. The efficiency of the reac-
tion was characterized by the overall yields which ranged
The next step in the synthetic pathway requires the trans-
formation of the carboxylic acid group of 3 into an amine.
A Curtius rearrangement could be suitable to achieve this
objective.
Synthesis 2013, 45, 2557–2566
© Georg Thieme Verlag Stuttgart · New York

PAPER
N-3-Substituted Pyrido[1′,2′:1,5]pyrazolo[3,4-d]pyrimidine-2,4(1H,3H)-diones
2559
from 51% to 81%. Substituted benzylamines and anilines
gave the best results (Table 1, entries 1–3, 5 and 6); the
condensation was poorly sensitive to the steric and elec-
tronic effects of aniline substituents. The use of n-butyl-
amine led to a small decrease in the efficiency of the
condensation reaction (Table 1, entry 4). The same behav-
ior was observed when 2- and 4-aminopyridines as deac-
tivated nucleophiles were used, but increasing the reaction
time to 6 hours led to the desired ureas 11–14 in satisfac-
tory yields (Table 1, entries 7–10).
CO2Me
CON3
1) ClCO2Et, Et3N
THF, 1.5 h, –10 °C
3
N
N
2) NaN3, H2O
r.t., 1.5 h
4
CO2Me
1) toluene, reflux, 2 h
NHCONHR
N
2) RNH2, CH2Cl2, r.t., 3 h
51–81%
N
5–14
Scheme 3 Synthesis of C-2-aminated compounds 5–14
Table 1 Synthesis of C-2-Aminated Derivatives of Type IX and N-3-Substituted Pyrimidinediones of Type V
Entry Nucleophile
C-2-Aminated derivatives
of type IX
Yielda,b N-3-Substituted pyrimidinediones
Yieldb
(%)
(%)
of type V
CO2Me
OMe
O
OMe
N
1
5
6
7
8
81
17
18
19
20
92
97
70
63
NH
O
H
N
OMe
O
N
H2N
N
NH
N
N
N
N
CO2Me
NH
F
O
F
N
2
H
N
63
76
64
F
O
N
H2N
N
NH
O
N
CO2Me
NH
Cl
O
Cl
N
3
H
N
Cl
O
N
H2N
N
NH
O
N
CO2Me
NH
O
N
H2N
4
H
N
O
N
N
NH
O
N
N
N
N
CO2Me
NH
O
H
N
N
N
5
9
77
73
21
22
94
93
N
O
H2N
O
NH
N
CO2Me
NH
O
OMe
H
N
OMe
N
N
6
10
N
H2N
O
O
OMe
NH
N
© Georg Thieme Verlag Stuttgart · New York
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R. Belaroussi et al.
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Table 1 Synthesis of C-2-Aminated Derivatives of Type IX and N-3-Substituted Pyrimidinediones of Type V (continued)
Entry Nucleophile
C-2-Aminated derivatives
of type IX
Yielda,b N-3-Substituted pyrimidinediones
Yieldb
(%)
(%)
of type V
CO2Me
N
O
NH
O
7
11
12
51c
N
23
24
86
84
H
N
N
N
O
H2N
N
NH
N
N
N
Br
CO2Me
NH
Br
N
N
H
N
O
53c
N
8
N
N
Br
O
O
H2N
H2N
H2N
N
NH
N
N
Cl
CO2Me
NH
Cl
H
N
N
N
O
9
13
14
65c
25
26
82
82
N
N
N
O
O
N
NH
Cl
N
N
N
CO2Me
NH
N
O
H
10
66c
N
N
N
N
O
O
NH
N
N
N
a Yield calculated from 3.
b Yield of isolated compound.
c Reaction time was increased to 6 h.
The process from 3 and the reaction with 4-methoxyben- Possessing the method to prepare the intermediate isocy-
zylamine gave a white solid that was used to isolate a anate in a quantitative manner, we then decided to en-
single crystal of urea 5 (Figure 4).17 The X-ray crystal hance the usefulness of the isocyanate and form a Boc-
structure analysis confirmed the substitution of the pyr- protected amine of type IX. After addition of excess tert-
azolo[1,5-a]pyridine by a nitrogen atom at C-2, the urea butyl alcohol to the crude derivative 4, the Boc-protected
formation and the presence of the ester function at C-3.
-amino ester 15 was isolated after 6 hours at reflux in an
excellent 85% yield (Scheme 4). Subsequent saponifica-
tion gave acid 16 quantitatively after an acidic neutraliza-
tion.
Ureas 5–14 were used in a final step to build the pyrimi-
dine ring and achieve the construction of the N-3-substituted
pyrido[1′,2′:1,5]pyrazolo[3,4-d]pyrimidine-2,4(1H,3H)-
dione library of type V (Scheme 5). Cyclization by direct
heating of a toluene mixture containing the just-synthe-
sized urea always failed, showing that purification of the
urea remains essential. In refluxing anhydrous ethanol in
the presence of a stoichiometric amount of sodium etha-
nolate, the annulation of 5 occurred smoothly and, after 8
hours, the desired 3-(p-methoxybenzyl)-protected pyrim-
idinedione 17 was isolated in a near quantitative manner.
Other N-3-benzyl-, N-3-phenyl- and N-3-pyridinyl-substi-
tuted pyrimidinediones 18–24 were formed in yields up to
Figure 4 Single-crystal X-ray analysis of compound 517
Synthesis 2013, 45, 2557–2566
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PAPER
N-3-Substituted Pyrido[1′,2′:1,5]pyrazolo[3,4-d]pyrimidine-2,4(1H,3H)-diones
2561
CO2Me
NHBoc
CO2Me
CON3
OMe
O
O
t-BuOH
NH
NH
N
N
N
O
reflux, 6 h
85%
O
N
N
AlCl3, anisole
15
NH
4
N
N
N
r.t.
quant.
N
NaOH, MeOH, H2O
40 °C, 12 h
quant.
17
27
POCl3, PCl5
reflux
CO2H
71%
Cl
NHBoc
N
N
N
Cl
16
N
N
Scheme 4 Synthesis of compound 16
N
28
Scheme 6 Preparation of other useful scaffolds
97% (Table 1). A slight decrease in efficiency was ob-
served with 4-chlorobenzyl or n-butyl substitution (Table
1, entries 3 and 4) and was attributed to difficulties during
the recovery of pure material.
1H and 13C NMR spectra were recorded on a Bruker DPX 250 MHz
or 400 MHz instrument using CDCl3 or DMSO-d6 as solvent. The
chemical shifts are reported in parts per million (δ scale) and all
coupling constant (J) values are in hertz (Hz). The following abbre-
viations are used to explain the multiplicities: s (singlet), d (dou-
blet), t (triplet), q (quartet), m (multiplet), dd (doublet doublet).
Melting points are uncorrected. IR absorption spectra were obtained
on a Perkin Elmer Paragon 1000 PC instrument and values are re-
ported in cm–1. HRMS were recorded on a Bruker maXis mass spec-
trometer. Monitoring of the reactions was performed using Merck
silica gel 60 F254 TLC plates. Spots were visualized by UV light at
254 nm and 356 nm. Column chromatography was performed using
Merck silica gel 60 (0.063–0.200 mm).
R
O
CO2Me
NHCONHR
N
NaOEt (1.0 equiv)
O
NH
EtOH, reflux, 8 h
63–97%
N
N
N
N
V
5–14
Scheme 5 Preparation of N-3-substituted pyrimidinediones of type
V
In order to fully complete our investigations in the pyrim-
idinedione series, we present as an additional result the
transformation of 17 into a very useful C-2,C-4-dichlori-
nated derivative, a good platform to explore chemical di-
versity (Scheme 6). With aluminum chloride and in the
presence of anisole at room temperature, the p-methoxy-
benzyl group of 17 was cleaved in a quantitative manner.
After some chlorination assays, we found that the previ-
ously unknown 2,4-dichloro derivative 28 could be ob-
tained by the reaction of dione 27 in refluxing phosphorus
oxychloride in a good 71% yield.
Dimethyl Pyrazolo[1,5-a]pyridine-2,3-dicarboxylate (2)
To a stirred soln of 1-aminopyridinium iodide (1; 1.0 g, 4.5 mmol)
in anhyd DMF (10 mL) were added anhyd K2CO3 (0.87 g, 6.3
mmol) and DMAD (0.96 g, 6.7 mmol). The mixture was stirred at
r.t. for 18 h. The solvent was evaporated in vacuo; then, the residue
was purified by flash chromatography (PE–EtOAc, 8:2) to give 2 as
yellow crystals; yield: 744 mg (71%).
Mp 64–66 °C (Lit.15a 64–68 °C, Lit.15b 57–57.5 °C).
Rf = 0.13 (PE–EtOAc, 8:2).
IR (ATR diamond): 3111, 1730, 1685, 1484, 1364, 1213, 1079,
995, 814 cm–1.
HRMS (ESI): m/z [M + H]+ calcd for C11H10N2O4: 235.0713;
found: 235.0716.
In this work, we have examined the construction of rare
C-2-aminated pyrazolo[1,5-a]pyridine derivatives which
were used to prepare a library of N-3-substituted pyri-
do[1′,2′:1,5]pyrazolo[3,4-d]pyrimidine-2,4(1H,3H)-diones,
by four successive steps. A regio-controlled saponifica-
tion followed by a Curtius rearrangement and amine con-
densation were successfully performed to achieve this
result. Regioselectivity of the saponification was proved
and ORTEP representations of two key intermediates
were provided. In addition, other reactions led to interest-
ing Boc-protected 2-aminopyrazolo[1,5-a]pyridines and
to pyrido[1′,2′:1,5]pyrazolo[3,4-d]pyrimidines substitut-
ed by chlorine or oxo groups at C-2 and C-4, as novel use-
ful scaffolds. Assays are in progress to explore the
reactivity of such compounds.
3-(Methoxycarbonyl)pyrazolo[1,5-a]pyridine-2-carboxylic
Acid (3)
To a mixture of 215 (500 mg, 2.1 mmol) in MeOH (30 mL) was add-
ed NaOH (85.2 mg, 2.1 mmol) in one portion. The solution was
stirred at r.t. for 3 h, then the solvent was removed. The residue was
dissolved in H2O (10 mL) and the mixture was acidified to pH 1 us-
ing 10% aq HCl. Extractions were performed with CH2Cl2 (3 × 20
mL) and the combined organic layers were concentrated in vacuo to
give 3 as a white solid; yield: 429 mg (91%).
Mp 220–222 °C.
Rf = 0.1 (PE–EtOAc, 8:2).
IR (ATR diamond): 3091, 3024, 2574, 1745, 1610, 1486, 1443,
1368, 1298, 1226, 1090, 962, 819, 771, 671, 626 cm–1.
© Georg Thieme Verlag Stuttgart · New York
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2562
R. Belaroussi et al.
PAPER
1H NMR (400 MHz, CDCl3): δ = 14.62 (s, 1 H, CO2H), 8.71 (d,
J = 8.0 Hz, 1 H), 8.16 (d, J = 8.0 Hz, 1 H), 7.61 (t, J = 8.0 Hz, 1 H),
7.19 (t, J = 8.0 Hz, 1 H), 4.12 (s, 3 H, OCH3).
13C NMR (100.6 MHz, CDCl3): δ = 167.9 (CO), 160.2 (CO), 147.0
(Cq), 141.9 (Cq), 130.1 (CH), 129.5 (CH), 120.4 (CH), 116.4 (CH),
101.1 (Cq), 53.5 (CH3).
(CH), 129.0 (CH), 128.6 (CH), 128.6 (CH), 118.0 (CH), 115.5
(CH), 115.3 (CH), 113.3 (CH), 88.5 (Cq), 51.4 (CH3), 43.4 (CH2).
HRMS (ESI): m/z [M + H]+ calcd for C17H15FN4O3: 343.1201;
found: 343.1202.
Methyl 2-[3-(4-Chlorobenzyl)ureido]pyrazolo[1,5-a]pyridine-
3-carboxylate (7)
Compound 7 was prepared using 4-chlorobenzylamine and was ob-
tained as a beige solid after flash chromatography (PE–EtOAc, 3:7);
yield: 1.22 g (76%).
HRMS (ESI): m/z [M + H]+ calcd for C10H8N2O4: 221.0557; found:
221.0558.
Ureas 5–14; General Procedure
Mp 168–170 °C.
A soln of acid 3 (1.0 g, 4.5 mmol) and Et3N (597 mg, 5.90 mmol)
in anhyd THF (15 mL) was cooled at –10 °C. After 5 min, ethyl
chloroformate (739 mg, 6.8 mmol) was added dropwise and the re-
action mixture was stirred at –10 °C for 1.5 h. After complete con-
version (TLC), a soln of sodium azide (501 mg, 7.7 mmol) in H2O
(2 mL) was then added in one portion. After 1.5 h at r.t., the result-
ing heterogeneous mixture was filtered, the organic solvent was re-
moved under reduced pressure without any heating, and the
aqueous phase was extracted with EtOAc (3 × 25 mL). The com-
bined organic layers were dried over MgSO4, filtered and carefully
concentrated in vacuo. The crude acyl azide 4 was dissolved in an-
hyd toluene (10 mL) and the solution was refluxed for 2 h, then
cooled to r.t. The resulting mixture was evaporated without any
heating. The crude residue was dissolved in anhyd CH2Cl2 (15 mL),
the desired amine (1.0 equiv) was added and the reaction mixture
was stirred at r.t. for 3 h. The solution was evaporated to dryness and
the residue was purified by flash chromatography to afford com-
pound 5–14.
Rf = 0.5 (PE–EtOAc, 3:7).
IR (ATR diamond): 3317, 3117, 2954, 2848, 1664, 1531, 1442,
1308, 1231, 1127, 1011, 907, 839, 782, 749, 695, 652 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.62 (s, 1 H, NH), 8.50 (s, 1 H,
NH), 8.27 (d, J = 6.9 Hz, 1 H), 7.93 (d, J = 8.8 Hz, 1 H), 7.41 (t,
J = 8.7 Hz, 1 H), 7.35–7.27 (m, 4 H), 6.90 (td, J = 6.9, 1.3 Hz, 1 H),
4.59 (d, J = 5.8 Hz, 2 H, CH2N), 3.94 (s, 3 H, OCH3).
13C NMR (63 MHz, CDCl3): δ = 165.5 (CO), 155.4 (Cq), 154.4
(CO), 142.2 (Cq), 139.1 (Cq), 134.3 (Cq), 130.2 (2 × CH), 130.1
(2 × CH), 130.0 (2 × CH), 119.4 (CH), 114.8 (CH), 89.9 (Cq), 52.8
(CH3), 44.9 (CH2).
HRMS (ESI): m/z [M + H]+ calcd for C17H15ClN4O3: 359.0905;
found: 359.0906.
Methyl 2-(3-Butylureido)pyrazolo[1,5-a]pyridine-3-carboxyl-
ate (8)
Compound 8 was prepared using n-butylamine and was obtained as
a beige solid after flash chromatography (PE–EtOAc, 3:7); yield:
835 mg (64%).
Methyl 2-[3-(4-Methoxybenzyl)ureido]pyrazolo[1,5-a]pyri-
dine-3-carboxylate (5)
Compound 5 was prepared using 4-methoxybenzylamine and was
obtained as a white solid after flash chromatography (PE–EtOAc,
3:7); yield: 1.29 g (81%).
Mp 98 °C.
Rf = 0.53 (PE–EtOAc, 2:8).
Mp 130–132 °C.
IR (ATR diamond): 3332, 3118, 2953, 2872, 1669, 1531, 1441,
1290, 1234, 1114, 1015, 893, 781, 666 cm–1.
Rf = 0.33 (CH2Cl2–MeOH, 9.8:0.2).
1H NMR (400 MHz, CDCl3): δ = 8.50 (s, 1 H, NH), 8.33 (d, J = 8.0
Hz, 1 H), 8.08 (s, 1 H, NH), 7.95 (d, J = 8.0 Hz, 1 H), 7.43 (t, J = 8.0
Hz, 1 H), 6.92 (t, J = 8.0 Hz, 1 H), 3.98 (s, 3 H, OCH3), 3.44–3.40
(m, 2 H, CH2), 1.66–1.62 (m, 2 H, CH2), 1.48–1.44 (m, 2 H, CH2),
0.99 (t, J = 7.0 Hz, 3 H, CH3).
13C NMR (101 MHz, CDCl3): δ = 164.0 (CO), 153.9 (2 × Cq),
140.8 (CO), 128.6 (CH), 128.4 (CH), 117.9 (CH), 113.2 (CH), 88.4
(Cq), 51.3 (CH3), 40.0 (CH2), 32.0 (CH2), 20.2 (CH2), 13.8 (CH3).
IR (ATR diamond): 3326, 1695, 1546, 1514, 1442, 1296, 1238,
1105, 782, 752, 645 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 8.69 (s, 1 H, NH), 8.52 (s, 1 H,
NH), 8.30 (d, J = 8.0 Hz, 1 H), 7.85 (d, J = 8.0 Hz, 1 H), 7.57 (d,
J = 8.0 Hz, 1 H), 7.18 (d, J = 7.5 Hz, 2 H), 7.09 (t, J = 8.0 Hz, 1 H),
6.89 (d, J = 7.5 Hz, 2 H), 4.37 (d, J = 8.0 Hz, 2 H, CH2N), 3.86 (s,
3 H, OCH3), 3.72 (s, 3 H, OCH3).
13C NMR (101 MHz, DMSO-d6): δ = 164.4 (CO), 158.7 (CO),
153.2 (Cq), 152.9 (Cq), 140.1 (Cq), 131.9 (Cq), 130.1 (2 × CH),
128.9 (2 × CH), 117.4 (CH), 114.5 (CH), 114.2 (2 × CH), 87.8
(Cq), 55.5 (CH3), 51.7 (CH3), 43.0 (CH2).
HRMS (ESI): m/z [M + H]+ calcd for C14H18N4O3: 291.1452;
found: 291.1454.
HRMS (ESI): m/z [M + H]+ calcd for C18H18N4O4: 355.1401;
found: 355.1403.
Methyl 2-(3-Phenylureido)pyrazolo[1,5-a]pyridine-3-carboxyl-
ate (9)
Compound 9 was prepared using aniline and was obtained as a
white solid after flash chromatography (PE–EtOAc, 3:7); yield:
1.07 g (77%).
Methyl 2-[3-(4-Fluorobenzyl)ureido]pyrazolo[1,5-a]pyridine-3-
carboxylate (6)
Compound 6 was prepared using 4-fluorobenzylamine and was ob-
tained as a beige solid after flash chromatography (PE–EtOAc, 3:7);
yield: 969 mg (63%).
Mp 153–155 °C.
Rf = 0.7 (PE–EtOAc, 2:8).
IR (ATR diamond): 3339, 3278, 3100, 2163, 1794, 1667, 1541,
1447, 1323, 1208, 1117, 1039, 920, 783, 689, 613 cm–1.
Mp 142–144 °C.
Rf = 0.33 (PE–EtOAc, 3:7).
1H NMR (400 MHz, CDCl3): δ = 10.25 (s, 1 H, NH), 8.68 (s, 1 H,
NH), 8.39 (dt, J = 6.8, 0.9 Hz, 1 H), 7.98 (d, J = 8.9 Hz, 1 H), 7.62
(dd, J = 8.5, 1.0 Hz, 2 H), 7.46 (ddd, J = 8.8, 7.0, 1.1 Hz, 1 H), 7.33–
7.38 (m, 2 H), 7.11 (t, J = 7.4 Hz, 1 H), 6.97 (td, J = 6.9, 1.4 Hz, 1
H), 3.96 (s, 3 H, OCH3).
13C NMR (101 MHz, CDCl3): δ = 153.4 (CO), 151.2 (Cq), 140.8
(CO), 138.3 (Cq), 129.0 (2 × CH), 128.8 (CH), 128.7 (CH), 123.7
(CH), 120.2 (2 × CH), 118.2 (CH), 113.8 (CH), 105.9 (Cq), 88.7
(Cq), 51.4 (CH3).
IR (ATR diamond): 3329, 3303, 2955, 2162, 1664, 1533, 1443,
1355, 1305, 1219, 1091, 840, 781, 687 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.61 (s, 1 H, NH), 8.48 (s, 1 H,
NH), 8.26 (d, J = 6.8 Hz, 1 H), 7.93 (d, J = 8.8 Hz, 1 H), 7.46–7.33
(m, 3 H), 7.02 (t, J = 8.7 Hz, 2 H), 6.89 (t, J = 6.9 Hz, 1 H), 4.59 (d,
J = 5.8 Hz, 2 H, CH2N), 3.94 (s, 3 H, OCH3).
13C NMR (101 MHz, CDCl3): δ = 164.05 (CO), 162.0 (d, J = 245.0
Hz, F-Cq), 157.0 (CO), 154.0 (Cq), 140.8 (Cq), 134.9 (Cq), 129.1
Synthesis 2013, 45, 2557–2566
© Georg Thieme Verlag Stuttgart · New York

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N-3-Substituted Pyrido[1′,2′:1,5]pyrazolo[3,4-d]pyrimidine-2,4(1H,3H)-diones
2563
HRMS (ESI): m/z [M + H]+ calcd for C16H14N4O3: 311.1139;
found: 311.1140.
HRMS (ESI): m/z [M + H]+ calcd for C15H12BrN5O3: 390.0196;
found: 390.0196.
Methyl 2-[3-(2-Methoxyphenyl)ureido]pyrazolo[1,5-a]pyri-
dine-3-carboxylate (10)
Compound 10 was prepared using o-anisidine and was obtained as
a light pink solid after flash chromatography (PE–EtOAc, 3:7);
yield: 1.12 g (73%).
Methyl 2-[3-(5-Chloropyridin-2-yl)ureido]pyrazolo[1,5-a]pyri-
dine-3-carboxylate (13)
Compound 13 was prepared using 2-amino-5-chloropyridine (reac-
tion time: 6 h) and was obtained as a white solid after flash chroma-
tography (PE–EtOAc, 3:7); yield: 1.01 g (65%).
Mp 222–224 °C.
Mp 232–234 °C.
Rf = 0.63 (PE–EtOAc, 2:8).
Rf = 0.26 (PE–EtOAc, 3:7).
IR (ATR diamond): 3425, 3344, 2949, 2162, 1825, 1671, 1601,
1533, 1377, 1344, 1207, 1110, 1025, 783, 751, 631 cm–1.
IR (ATR diamond): 3557, 3306, 3126, 2852, 1826, 1702, 1663,
1528, 1376, 1353, 1241, 1120, 1009, 833, 779, 635 cm–1.
1H NMR (400 MHz, CDCl3): δ = 10.67 (s, 1 H, NH), 8.64 (s, 1 H,
NH), 8.39 (dd, J = 7.7, 1.8 Hz, 1 H), 8.34 (d, J = 6.8 Hz, 1 H), 7.96
(d, J = 8.9 Hz, 1 H), 7.43 (t, J = 8.7 Hz, 1 H), 7.11–6.78 (m, 4 H),
4.00 (s, 3 H, OCH3), 3.96 (s, 3 H, OCH3).
13C NMR (101 MHz, CDCl3): δ = 164.1 (CO), 152.7 (CO), 151.1
(Cq), 148.5 (Cq), 140.8 (Cq), 128.6 (CH), 128.6 (CH), 128.5 (Cq),
123.0 (CH), 121.2 (CH), 119.9 (CH), 118.1 (CH), 113.5 (CH),
110.2 (CH), 88.6 (Cq), 56.1 (CH3), 51.4 (CH3).
1H NMR (250 MHz, CDCl3): δ = 10.83 (s, 1 H, NH), 8.94 (s, 1 H,
NH), 8.56 (d, J = 6.9 Hz, 1 H), 8.30 (d, J = 2.3 Hz, 1 H), 8.22 (d,
J = 8.9 Hz, 1 H), 7.98 (d, J = 8.9 Hz, 1 H), 7.69 (dd, J = 8.9, 2.6 Hz,
1 H), 7.49 (ddd, J = 8.9, 7.0, 1.1 Hz, 1 H), 6.99 (td, J = 6.9, 1.4 Hz,
1 H), 3.99 (s, 3 H, OCH3).
13C NMR (63 MHz, CDCl3): δ = 165.6 (CO), 153.7 (CO), 152.2
(Cq), 151.9 (Cq), 147.8 (CH), 142.0 (Cq), 139.3 (CH), 130.5 (CH),
130.3 (CH), 127.5 (Cq), 119.5 (CH), 116.0 (CH), 115.1 (CH), 90.3
(Cq), 52.9 (CH3).
HRMS (ESI): m/z [M + H]+ calcd for C17H16N4O4: 341.1244;
found: 341.1245.
HRMS (ESI): m/z [M + H]+ calcd for C15H12ClN5O3: 346.0701;
found: 346.0700.
Methyl 2-(3-Pyridin-2-ylureido)pyrazolo[1,5-a]pyridine-3-car-
boxylate (11)
Compound 11 was prepared using 2-aminopyridine (reaction time:
6 h) and was obtained as a white solid after flash chromatography
(PE–EtOAc, 3:7); yield: 716 mg (51%).
Methyl 2-(3-Pyridin-4-ylureido)pyrazolo[1,5-a]pyridine-3-car-
boxylate (14)
Compound 14 was prepared using 4-aminopyridine (reaction time:
6 h) and was obtained as a white solid after flash chromatography
(PE–EtOAc, 3:7); yield: 926 mg (66%).
Mp 242–244 °C.
Mp 178–180 °C.
Rf = 0.26 (PE–EtOAc, 3:7).
Rf = 0.1 (PE–EtOAc, 2:8).
IR (ATR diamond): 3323, 3251, 3118, 2952, 1697, 1669, 1531,
1432, 1305, 1207, 1154, 990, 782, 649, 619 cm–1.
IR (ATR diamond): 3327, 3189, 3104, 2960, 1713, 1678, 1537,
1339, 1242, 1131, 1034, 814, 780, 637 cm–1.
1H NMR (400 MHz, CDCl3): δ = 10.52 (s, 1 H, NH), 8.84 (s, 1 H,
NH), 8.54–8.48 (m, 2 H), 8.42 (d, J = 6.9 Hz, 1 H), 7.98 (d, J = 8.9
Hz, 1 H), 7.58–7.55 (m, 2 H), 7.49 (ddd, J = 8.5, 7.0, 1.1 Hz, 1 H),
7.01 (td, J = 7.0, 1.4 Hz, 1 H), 3.97 (s, 3 H, OCH3).
1H NMR (400 MHz, CDCl3): δ = 10.67 (s, 1 H, NH), 8.88 (s, 1 H,
NH), 8.52 (dd, J = 6.8, 1.3 Hz, 1 H), 8.39–8.30 (m, 1 H), 8.16 (s, 1
H), 7.94 (d, J = 8.8 Hz, 1 H), 7.71 (ddd, J = 8.7, 7.4, 2.0 Hz, 1 H),
7.52–7.37 (m, 1 H), 7.05–6.99 (m, 1 H), 6.94 (td, J = 7.1, 1.3 Hz, 1
H), 3.96 (s, 3 H, OCH3).
13C NMR (101 MHz, CDCl3): δ = 164.1 (CO), 152.3 (CO), 152.1
(Cq), 150.9 (Cq), 147.7 (CH), 140.6 (Cq), 138.2 (CH), 129.1 (CH),
128.7 (CH), 119.0 (CH), 118.0 (CH), 113.8 (CH), 113.5 (CH), 88.8
(Cq), 51.4 (CH3).
13C NMR (101 MHz, CDCl3): δ = 164.1 (CO), 152.4 (CO), 150.8
(Cq), 150.6 (2 × CH), 145.5 (Cq), 140.7 (Cq), 129.0 (CH), 128.7
(CH), 118.3 (CH), 113.9 (CH), 113.8 (2 × CH), 88.9 (Cq), 51.6
(CH3).
HRMS (ESI): m/z [M + H]+ calcd for C15H13N5O3: 312.1091;
found: 312.1092.
HRMS (ESI): m/z [M + H]+ calcd for C15H13N5O3: 312.1091;
found: 312.1092.
Methyl 2-[3-(4-Bromopyridin-2-yl)ureido]pyrazolo[1,5-a]pyri-
dine-3-carboxylate (12)
Compound 12 was prepared using 2-amino-4-bromopyridine (reac-
tion time: 6 h) and was obtained as a white solid after flash chroma-
tography (PE–EtOAc, 3:7); yield: 930 mg (53%).
Methyl 2-(tert-Butoxycarbonylamino)pyrazolo[1,5-a]pyridine-
3-carboxylate (15)
Compound 15 was prepared from acid 3. After the initial acyl azide
4 synthesis, as described in the general procedure for ureas 5–14, t-
BuOH (20 mL) was added and the mixture was refluxed for 6 h. The
solvent was evaporated and the crude material was purified by col-
umn chromatography (PE–EtOAc, 3:7) to give 15 as a white solid;
yield: 1.11 g (85%).
Mp 172–174 °C.
Rf = 0.26 (PE–EtOAc, 3:7).
IR (ATR diamond): 3564, 3307, 3127, 2958, 2851, 1702, 1661,
1528, 1443, 1373, 1240, 1117, 915, 831, 737, 630 cm–1.
Mp 183–185 °C.
Rf = 0.6 (PE–EtOAc, 2:8).
1H NMR (400 MHz, CDCl3): δ = 10.82 (s, 1 H, NH), 8.92 (s, 1 H,
NH), 8.55 (dd, J = 6.8, 0.9 Hz, 1 H), 8.38 (d, J = 2.4 Hz, 1 H), 8.17
(d, J = 8.6 Hz, 1 H), 7.98 (d, J = 8.8 Hz, 1 H), 7.81 (dd, J = 8.9, 2.4
Hz, 1 H), 7.48 (ddd, J = 8.8, 7.0, 1.0 Hz, 1 H), 6.99 (td, J = 6.9, 1.3
Hz, 1 H), 3.99 (s, 3 H, OCH3).
13C NMR (101 MHz, CDCl3): δ = 171.3 (CO), 165.8 (Cq), 152.2
(CO), 150.9 (Cq), 150.8 (Cq), 148.6 (CH), 140.6 (CH), 129.1 (CH),
128.9 (CH), 118.1 (CH), 115.1 (CH), 113.9 (Cq), 113.7 (CH), 88.8
(Cq), 51.5 (CH3).
IR (ATR diamond): 3343, 3084, 3042, 2984, 1742, 1667, 1530,
1462, 1389, 1285, 1150, 1054, 784, 697, 626 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 9.03 (s, 1 H, NH), 8.75 (d,
J = 6.8 Hz, 1 H), 7.91 (d, J = 8.8 Hz, 1 H), 7.59 (ddd, J = 8.7, 7.0,
1.0 Hz, 1 H), 7.12 (td, J = 6.9, 1.4 Hz, 1 H), 3.83 (s, 3 H, OCH3),
1.48 (s, 9 H, 3 × CH3).
13C NMR (100 MHz, DMSO-d6): δ = 163.9 (CO), 151.3 (CO),
150.5 (Cq), 139.9 (Cq), 129.7 (CH), 128.9 (CH), 117.2 (CH), 114.1
(CH), 90.7 (Cq), 80.2 (Cq), 51.2 (CH3), 27.8 (3 × CH3).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2557–2566

2564
R. Belaroussi et al.
PAPER
HRMS (ESI): m/z [M + H]+ calcd for C14H17N3O4: 292.1292;
found: 292.1292.
IR (ATR diamond): 3209, 3119, 2917, 2110, 1710, 1668, 1507,
1436, 1336, 1220, 1154, 1088, 921, 861, 748 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 12.14 (s, 1 H, NH), 8.86 (d,
J = 6.9 Hz, 1 H), 7.93 (d, J = 8.6 Hz, 1 H), 7.68 (t, J = 8.0 Hz, 1 H),
7.38 (dd, J = 8.3, 5.4 Hz, 2 H), 7.23 (t, J = 7.0 Hz, 1 H), 7.13 (t,
J = 8.7 Hz, 2 H), 5.04 (s, 2 H, CH2).
13C NMR (101 MHz, DMSO-d6): δ = 161.7 (d, J = 242.6 Hz, F-Cq),
158.7 (CO), 152.8 (CO), 152.0 (Cq), 138.8 (Cq), 134.6 (Cq), 130.6
(CH), 130.1 (CH), 130.0 (CH), 129.9 (CH), 116.7 (CH), 115.6
(CH), 115.5 (CH), 115.3 (CH), 89.8 (Cq), 42.3 (CH2).
2-(tert-Butoxycarbonylamino)pyrazolo[1,5-a]pyridine-3-car-
boxylic Acid (16)
In a round-bottomed flask, compound 15 (1.2 g, 4.1 mmol) was dis-
solved in MeOH (15 mL). Aq 2 N NaOH (3.5 equiv) was added and
the reaction mixture was stirred overnight at 40 °C. The solvent was
evaporated on a rotary evaporator and H2O (20 mL) was added to
the remaining material. The solution was acidified with 1 M HCl
until pH 2 and the mixture was extracted with CH2Cl2 (3 × 100
mL). The combined extracts were dried over MgSO4 and concen-
trated to give 16 as a pink solid (1.14 g) in a quantitative yield.
HRMS (ESI): m/z [M + H]+ calcd for C16H11FN4O2: 311.0939;
found: 311.0939.
Mp 258–260 °C.
3-(4-Chlorobenzyl)pyrido[1′,2′:1,5]pyrazolo[3,4-d]pyrimidine-
2,4(1H,3H)-dione (19)
Compound 19 was prepared starting from compound 7 and was iso-
lated as a white solid; yield: 229 mg (70%).
Rf = 0.23 (PE–EtOAc, 2:8).
IR (ATR diamond): 3335, 3080, 2980, 2165, 1748, 1655, 1568,
1530, 1481, 1339, 1289, 1255, 1130, 1055, 919, 861, 787, 752, 699
cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 9.05 (s, 1 H, NH), 8.70 (d,
J = 8.0 Hz, 1 H), 7.85 (d, J = 8.0 Hz, 1 H), 7.51 (t, J = 8.0 Hz, 1 H),
7.06 (t, J = 8.0 Hz, 1 H), 1.50 (s, 9 H, 3 × CH3).
13C NMR (100 MHz, DMSO-d6): δ = 165.4 (CO), 151.7 (CO),
149.9 (Cq), 139.9 (Cq), 129.6 (CH), 128.7 (CH), 117.2 (CH), 113.8
(CH), 90.1 (Cq), 80.3 (Cq), 27.8 (3 × CH3).
Mp 343–345 °C.
Rf = 0.3 (CH2Cl2–MeOH, 9.8:0.2).
IR (ATR diamond): 3105, 3073, 2912, 2853, 1717, 1651, 1432,
1375, 1294, 1087, 922, 797, 694 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 12.17 (s, 1 H, NH), 8.86 (d,
J = 6.8 Hz, 1 H), 7.93 (d, J = 8.7 Hz, 1 H), 7.77–7.63 (m, 1 H),
7.48–7.24 (m, 4 H), 7.23 (td, J = 7.0, 1.4 Hz, 1 H), 5.05 (s, 2 H,
CH2).
HRMS (ESI): m/z [M + H]+ calcd for C13H15N3O4: 278.1132;
found: 278.1135.
13C NMR (101 MHz, DMSO-d6): δ = 158.8 (CO), 153.2 (CO),
152.2 (Cq), 138.9 (Cq), 137.5 (Cq), 132.0 (Cq), 130.7 (CH), 129.9
(CH), 129.8 (2 × CH), 128.7 (2 × CH), 116.8 (CH), 115.6 (CH),
89.9 (Cq), 42.5 (CH2).
HRMS (ESI): m/z [M + H]+ calcd for C16H11ClN4O2: 327.0643;
found: 327.0644.
N-3-Substituted Pyrido[1′,2′:1,5]pyrazolo[3,4-d]pyrimidine-
2,4(1H,3H)-diones 17–26; General Procedure
In a round-bottomed flask, compound 5–14 (1.0 mmol) was dis-
solved in anhyd EtOH (10 mL) and 2.68 M NaOEt in EtOH (380
μL, 1.0 mmol) was added. The reaction mixture was refluxed for 8
h, and the solvent was distilled under reduced pressure. To the crude
residue, a mixture of H2O–AcOH (10 mL, 8:2) was added. The pre-
cipitate was collected by filtration and washed several times with
Et2O (3 × 10 mL) to yield compound 17–26.
3-Butylpyrido[1′,2′:1,5]pyrazolo[3,4-d]pyrimidine-2,4(1H,3H)-
dione (20)
Compound 20 was prepared starting from compound 8 and was iso-
lated as a white solid; yield: 163 mg (63%).
3-(4-Methoxybenzyl)pyrido[1′,2′:1,5]pyrazolo[3,4-d]pyrimi-
dine-2,4(1H,3H)-dione (17)
Mp 264 °C.
Compound 17 was prepared starting from compound 5 and was iso-
lated as a white solid; yield: 296 mg (92%).
Rf = 0.33 (CH2Cl2–MeOH, 9.8:0.2).
IR (ATR diamond): 3241, 3191, 2948, 2867, 1708, 1654, 1436,
1349, 1286, 1084, 926, 749, 695 cm–1.
Mp 312–314 °C.
Rf = 0.3 (CH2Cl2–MeOH, 9.8:0.2).
1H NMR (400 MHz, DMSO-d6): δ = 12.03 (s, 1 H, NH), 8.83 (d,
J = 6.9 Hz, 1 H), 7.92 (d, J = 8.6 Hz, 1 H), 7.66 (t, J = 7.9 Hz, 1 H),
7.20 (t, J = 6.8 Hz, 1 H), 3.86 (t, J = 7.4 Hz, 2 H, CH2), 1.58–1.51
(m, 2 H, CH2), 1.35–1.26 (m, 2 H, CH2), 0.91 (t, J = 7.4 Hz, 3 H,
CH3).
13C NMR (101 MHz, DMSO-d6): δ = 158.8 (CO), 152.8 (CO),
152.0 (Cq), 138.8 (Cq), 130.6 (CH), 129.8 (CH), 116.7 (CH), 115.4
(CH), 89.9 (Cq), 39.6 (CH2), 30.3 (CH2), 20.1 (CH2), 14.2 (CH3).
IR (ATR diamond): 3219, 3117, 2996, 2804, 1978, 1703, 1638,
1511, 1433, 1320, 1245, 1180, 919, 856, 779, 695 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 10.07 (s, 1 H, NH), 8.83 (d,
J = 8.0 Hz, 1 H), 8.35 (d, J = 8.0 Hz, 1 H), 7.65 (t, J = 8.0 Hz, 1 H),
7.32–7.30 (m, 3 H), 6.89 (d, J = 7.5 Hz, 2 H), 4.49 (d, J = 8.0 Hz, 2
H, CH2N), 3.72 (s, 3 H, OCH3).
13C NMR (100 MHz, DMSO-d6): δ = 163.2 (CO), 162.1 (CO),
158.4 (Cq), 144.6 (Cq), 142.6 (Cq), 130.0 (Cq), 129.4 (CH), 129.0
(2 × CH), 128.9 (CH), 119.7 (CH), 116.7 (CH), 113.7 (2 × CH),
103.7 (Cq), 55.0 (CH3), 42.3 (CH2).
HRMS (ESI): m/z [M + H]+ calcd for C13H14N4O2: 259.1190;
found: 259.1191.
3-Phenylpyrido[1′,2′:1,5]pyrazolo[3,4-d]pyrimidine-
2,4(1H,3H)-dione (21)
Compound 21 was prepared starting from compound 9 and was iso-
lated as a white solid; yield: 261 mg (94%).
HRMS (ESI): m/z [M + H]+ calcd for C17H14N4O3: 323.1139;
found: 323.1140.
3-(4-Fluorobenzyl)pyrido[1′,2′:1,5]pyrazolo[3,4-d]pyrimidine-
2,4(1H,3H)-dione (18)
Mp 361–363 °C.
Compound 18 was prepared starting from compound 6 and was iso-
lated as a white solid; yield: 300 mg (97%).
Rf = 0.3 (CH2Cl2–MeOH, 9.8:0.2).
IR (ATR diamond): 3108, 2853, 2796, 2162, 1714, 1667, 1555,
1493, 1446, 1292, 1120, 817, 773, 692, 613 cm–1.
Mp >370 °C.
Rf = 0.3 (CH2Cl2–MeOH, 9.8:0.2).
1H NMR (400 MHz, DMSO-d6): δ = 12.15 (s, 1 H, NH), 8.90 (d,
J = 6.9 Hz, 1 H), 7.89 (d, J = 8.7 Hz, 1 H), 7.69 (t, J = 8.0 Hz, 1 H),
Synthesis 2013, 45, 2557–2566
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N-3-Substituted Pyrido[1′,2′:1,5]pyrazolo[3,4-d]pyrimidine-2,4(1H,3H)-diones
2565
7.48 (t, J = 7.4 Hz, 2 H), 7.47–7.39 (m, 1 H), 7.37–7.25 (m, 2 H),
7.24 (td, J = 7.0, 1.5 Hz, 1 H).
(CH), 130.4 (CH), 127.3 (CH), 120.7 (Cq), 116.8 (CH), 115.9 (CH),
90.0 (Cq).
13C NMR (101 MHz, DMSO-d6): δ = 158.9 (CO), 153.2 (CO),
152.1 (Cq), 139.1 (Cq), 136.4 (Cq), 130.7 (CH), 130.1 (CH), 130.0
(2 × CH), 129.2 (2 × CH), 128.3 (CH), 116.7 (CH), 115.6 (CH),
90.2 (Cq).
HRMS (ESI): m/z [M + H]+ calcd for C15H10N4O2: 279.0877;
found: 279.0876.
HRMS (ESI): m/z [M + H]+ calcd for C14H8BrN5O2: 357.9934;
found: 357.9933.
3-(5-Chloropyridin-2-yl)pyrido[1′,2′:1,5]pyrazolo[3,4-d]pyrim-
idine-2,4(1H,3H)-dione (25)
Compound 25 was prepared starting from compound 13 and was
isolated as a white solid; yield: 256 mg (82%).
3-(2-Methoxyphenyl)pyrido[1′,2′:1,5]pyrazolo[3,4-d]pyrimi-
dine-2,4(1H,3H)-dione (22)
Compound 22 was prepared starting from compound 10 and was
isolated as a white solid; yield: 286 mg (93%).
Mp 323–325 °C.
Rf = 0.16 (CH2Cl2–MeOH, 9.8:0.2).
IR (ATR diamond): 3186, 3092, 2919, 2161, 1724, 1672, 1565,
1423, 1289, 1016, 825, 744, 618 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 8.86 (d, J = 6.8 Hz, 1 H), 8.66
(d, J = 2.6 Hz, 1 H), 8.12 (dd, J = 8.4, 2.7 Hz, 1 H), 7.85 (d, J = 8.6
Hz, 1 H), 7.66 (t, J = 7.9 Hz, 1 H), 7.54 (d, J = 8.4 Hz, 1 H), 7.22
(td, J = 7.0, 1.2 Hz, 1 H).
Mp 330–332 °C.
Rf = 0.26 (CH2Cl2–MeOH, 9.8:0.2).
IR (ATR diamond): 3115, 3004, 2839, 1979, 1703, 1661, 1643,
1501, 1421, 1359, 1190, 1026, 874, 773, 610 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 12.12 (s, 1 H, NH), 8.90 (d,
J = 6.9 Hz, 1 H), 7.88 (d, J = 8.6 Hz, 1 H), 7.69 (t, J = 7.7 Hz, 1 H),
7.42 (t, J = 7.0 Hz, 1 H), 7.26–7.23 (m, 2 H), 7.16 (d, J = 8.1 Hz, 1
H), 7.04 (t, J = 7.5 Hz, 1 H), 3.73 (s, 3 H, OCH3).
13C NMR (101 MHz, DMSO-d6): δ = 159.1 (CO), 155.4 (CO),
152.8 (Cq), 149.3 (Cq), 148.2 (CH), 139.0 (Cq), 138.7 (CH), 131.3
(Cq), 130.6 (CH), 129.8 (CH), 126.8 (CH), 116.6 (CH), 115.4 (CH),
90.1 (Cq).
13C NMR (101 MHz, DMSO-d6): δ = 158.4 (CO), 155.7 (CO),
153.2 (Cq), 151.6 (Cq), 139.0 (Cq), 131.2 (CH), 130.7 (CH), 130.1
(CH), 124.8 (Cq), 120.8 (CH), 116.7 (CH), 115.6 (CH), 112.4 (CH),
99.9 (CH), 90.0 (Cq), 56.0 (CH3).
HRMS (ESI): m/z [M + H]+ calcd for C16H12N4O3: 309.0982;
found: 309.0982.
HRMS (ESI): m/z [M + H]+ calcd for C14H8ClN5O2: 314.0439;
found: 314.0440.
3-Pyridin-4-ylpyrido[1′,2′:1,5]pyrazolo[3,4-d]pyrimidine-
2,4(1H,3H)-dione (26)
Compound 26 was prepared starting from compound 14 and was
isolated as a white solid; yield: 229 mg (82%).
3-Pyridin-2-ylpyrido[1′,2′:1,5]pyrazolo[3,4-d]pyrimidine-
2,4(1H,3H)-dione (23)
Compound 23 was prepared starting from compound 11 and was
isolated as a white solid; yield: 240 mg (86%).
Mp >370 °C.
Rf = 0.06 (CH2Cl2–MeOH, 9.8:0.2).
IR (ATR diamond): 3108, 2987, 2854, 2161, 1976, 1723, 1654,
1510, 1350, 1287, 1113, 1010, 891, 767, 681 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 12.30 (s, 1 H, NH), 8.92 (d,
J = 6.8 Hz, 1 H), 8.71 (d, J = 6.0 Hz, 2 H), 7.90 (d, J = 8.6 Hz, 1 H),
7.71 (t, J = 7.5 Hz, 1 H), 7.44 (d, J = 6.0 Hz, 2 H), 7.26 (td, J = 7.0,
1.3 Hz, 1 H).
Mp 332–334 °C.
Rf = 0.13 (CH2Cl2–MeOH, 9.8:0.2).
IR (ATR diamond): 3183, 2992, 2856, 2162, 1725, 1652, 1588,
1422, 1349, 1138, 1014, 885, 775, 610 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 8.89 (d, J = 6.8 Hz, 1 H), 8.64–
8.57 (m, 1 H), 7.99 (td, J = 7.7, 2.0 Hz, 1 H), 7.87 (d, J = 8.6 Hz, 1
H), 7.68 (t, J = 8.4 Hz, 1 H), 7.49 (t, J = 6.5 Hz, 2 H), 7.24 (td,
J = 7.0, 1.2 Hz, 1 H).
13C NMR (101 MHz, DMSO-d6): δ = 158.9 (CO), 154.0 (CO),
152.3 (Cq), 150.2 (Cq), 149.7 (CH), 139.0 (Cq), 149.7 (CH), 130.7
(CH), 130.1 (CH), 125.3 (CH), 124.3 (CH), 116.7 (CH), 115.6
(CH), 90.1 (Cq).
13C NMR (101 MHz, DMSO-d6): δ = 158.2 (CO), 153.2 (CO),
151.5 (Cq), 150.8 (2 × CH), 144.3 (Cq), 139.1 (Cq), 130.9 (CH),
130.3 (CH), 125.5 (2 × CH), 116.8 (CH), 115.8 (CH), 90.1 (Cq).
HRMS (ESI): m/z [M + H]+ calcd for C14H9N5O2: 280.0829; found:
280.0830.
Pyrido[1′,2′:1,5]pyrazolo[3,4-d]pyrimidine-2,4(1H,3H)-dione
(27)
A mixture of compound 17 (50 mg, 0.15 mmol), anisole (8 mL) and
AlCl3 (200 mg, 10.0 equiv) was heated at r.t. for 12 h, and then
cooled to r.t. The reaction mixture was poured onto iced water under
vigorous stirring; the residue was collected by filtration, and
washed with H2O (2 × 20 mL) and acetone (2 × 20 mL) to obtain 27
as a white solid (30 mg) in quantitative yield.
HRMS (ESI): m/z [M + H]+ calcd for C14H9N5O2: 280.0829; found:
280.0828.
3-(4-Bromopyridin-2-yl)pyrido[1′,2′:1,5]pyrazolo[3,4-d]pyrim-
idine-2,4(1H,3H)-dione (24)
Compound 24 was prepared starting from compound 12 and was
isolated as a white solid; yield: 299 mg (84%).
Mp >370 °C.
Mp 338–340 °C.
Rf = 0.16 (CH2Cl2–MeOH, 9.8:0.2).
Rf = 0.16 (CH2Cl2–MeOH, 9.8:0.2).
IR (ATR diamond): 3179, 3023, 2846, 1721, 1648, 1582, 1447,
1318, 1292, 1145, 1018, 885, 748, 614 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 11.72 (s, 1 H, NH), 10.81 (s, 1
H, NH), 8.81 (d, J = 7.2 Hz, 1 H), 7.87 (d, J = 8.0 Hz, 1 H), 7.63 (t,
J = 7.9 Hz, 1 H), 7.18 (t, J = 7.0 Hz, 1 H).
13C NMR (101 MHz, DMSO-d6): δ = 159.6 (CO), 154.5 (CO),
152.3 (Cq), 138.6 (Cq), 130.6 (CH), 129.7 (CH), 116.7 (CH), 115.3
(CH), 90.3 (Cq).
IR (ATR diamond): 3193, 3067, 2914, 2162, 1716, 1680, 1422,
1292, 1134, 1008, 820, 760, 698 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 12.30 (s, 1 H, NH), 8.92 (d,
J = 6.9 Hz, 1 H), 8.76 (d, J = 2.5 Hz, 1 H), 8.27 (dd, J = 8.3, 2.6 Hz,
1 H), 7.89 (d, J = 8.6 Hz, 1 H), 7.71 (t, J = 7.9 Hz, 1 H), 7.53 (d,
J = 8.4 Hz, 1 H), 7.27 (t, J = 6.5 Hz, 1 H).
13C NMR (101 MHz, DMSO-d6): δ = 158.5 (CO), 153.3 (CO),
151.7 (Cq), 150.5 (CH), 149.0 (Cq), 141.7 (CH), 139.0 (Cq), 130.9
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2557–2566

2566
R. Belaroussi et al.
PAPER
Kazantsev, A. G.; Schemies, J.; Jung, M.; Esteller, M.
HRMS (ESI): m/z [M + H]+ calcd for C9H6N4O2: 203.0567; found:
203.0568.
ChemMedChem 2010, 5, 674.
(6) Zablocki, J.; Kalla, R.; Perry, T.; Palle, V.; Varkhedkar, V.;
Xiao, D.; Piscopio, A.; Maa, T.; Gimbel, A.; Hao, J.; Chu,
N.; Leung, K.; Zeng, D. Bioorg. Med. Chem. Lett. 2005, 15,
609.
(7) Feng, J.; Zhang, Z.; Wallace, M. B.; Stafford, J. A.; Kaldor,
S. W.; Kassel, D. B.; Navre, M.; Shi, L.; Skene, R. J.;
Asakawa, T.; Takeuchi, K.; Xu, R.; Webb, D. R.; Gwaltney,
S. L. J. Med. Chem. 2007, 50, 2297.
2,4-Dichloropyrido[1′,2′:1,5]pyrazolo[3,4-d]pyrimidine (28)
A mixture containing compound 27 (100 mg, 0.5 mmol) and PCl5
(412 mg, 2.0 mmol) in POCl3 (2 mL) was refluxed for 12 h, then
cooled to r.t. Excess POCl3 was evaporated, and the residue was
neutralized with aq Na2CO3 soln and extracted with CH2Cl2 (3 × 10
mL). The combined organic layers were dried over MgSO4 and con-
centrated in vacuo. The residue was purified by flash chromatogra-
phy (PE–EtOAc, 2:8) to afford 28 as a white solid; yield: 84 mg
(71%).
(8) Elzein, E.; Kalla, R. V.; Li, X.; Perry, T.; Gimbel, A.; Zeng,
D.; Lustig, D.; Leung, K.; Zablocki, J. J. Med. Chem. 2008,
51, 2267.
Mp >370 °C.
(9) Kiesman, W. F.; Zhao, J.; Conlon, P. R.; Dowling, J. E.;
Petter, R. C.; Lutterodt, F.; Jin, X.; Smits, G.; Fure, M.;
Jayaraj, A.; Kim, J.; Sullivan, G.; Linden, J. J. Med. Chem.
2006, 49, 7119.
(10) Bonache, M.-C.; Chamorro, C.; Velazquez, S.; Clercq, E.
D.; Balzarini, J.; Barrios, F. R.; Gago, F.; Camarasa, M.-J.;
San-Felix, A. J. Med. Chem. 2005, 48, 6653.
Rf = 0.46 (PE–EtOAc, 2:8).
IR (ATR diamond): 3054, 1645, 1585, 1507, 1387, 1290, 1182,
1010, 992, 786, 672 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 9.35 (d, J = 6.8 Hz, 1 H), 8.56
(d, J = 8.6 Hz, 1 H), 8.07 (t, J = 7.9 Hz, 1 H), 7.81 (t, J = 6.9 Hz, 1
H).
13C NMR (101 MHz, DMSO-d6, DEPT): δ = 131.67, 131.05,
121.62, 120.45.
(11) Liubchak, K.; Nazarenko, K.; Tolmachev, A.; Grygorenko,
O. O. Tetrahedron 2012, 68, 8564.
(12) (a) Molina, P.; Arques, A.; Hernandez, H. J. Heterocycl.
Chem. 1984, 21, 685. (b) Arques, A.; Hernandez, H.;
Molina, P.; Vilaplana, M. J. Synthesis 1981, 910.
(13) Jung, D. K.; Alberti, M. J. Int. Patent Appl. WO
2006086539, 2006; Chem. Abstr. 2006, 145, 249218.
(14) (a) Koike, T.; Takai, T.; Hoashi, Y. Int. Patent Appl. WO
2008136382, 2008; Chem. Abstr. 2008, 149, 556633.
(b) Thomas, A. P.; Breault, G. A.; Beattie, J. F.; Jewsbury,
P. J. Int. Patent Appl. WO 2001014375, 2000; Chem. Abstr.
2001, 134, 193444. (c) Tran-Dube, M.; Sach, N.; Ninkovic,
S.; Braganza, J. F.; Huang, Q.; Johnson, B.; Collins, M. R.
Tetrahedron Lett. 2012, 53, 4372. (d) Gmeiner, P.; Sommer,
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HRMS (ESI): m/z [M + H]+ calcd for C9H4Cl2N5: 238.9886; found:
238.9888.
Acknowledgment
We gratefully acknowledge support of this work by the Moroccan
Scientific and Technical Research Center (CNRST), Pôle RéPAM
and l’Office Méditerranéen de la Jeunesse (OMJ) through a doctoral
grant (R.B.).
References
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(17) Crystallographic data for the structures 3 and 5 have been
deposited with the Cambridge Crystallographic Data Centre
as supplementary publication nos. CCDC 931739 (3) and
932187 (5). Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK [Fax: +44(1223)336033; E-mail:
deposit@ccdc.cam.ac.uk].
Synthesis 2013, 45, 2557–2566
© Georg Thieme Verlag Stuttgart · New York