Microwave-assisted synthesis of fused pyrazolo[3,4-b]pyrazines by the reaction of ortho-aminonitrosopyrazoles and cyclic β-diketones

Article abstract of DOI:10.1016/j.tetlet.2012.04.083

Novel fused pyrazolo[3,4-b]pyrazines 3 were prepared by assisted microwave cyclocondensation reaction of ortho-aminonitrosopyrazoles 1 and cyclic β-diketones 2 in dimethylformamide. This protocol provides a simple procedure for the synthesis of the title compounds with the advantages of easy work-up, mild reaction conditions and good yields.

Full text of DOI:10.1016/j.tetlet.2012.04.083

Tetrahedron Letters 53 (2012) 3181–3187
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Tetrahedron Letters
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Microwave-assisted synthesis of fused pyrazolo[3,4-b]pyrazines
by the reaction of ortho-aminonitrosopyrazoles and cyclic b-diketones
⇑
Jairo Quiroga , Norha E. Sánchez, Paola Acosta, Braulio Insuasty, Rodrigo Abonia
Grupo de Investigación de Compuestos Heterocíclicos, Departamento de Química, Universidad del Valle, A.A. 25360 Cali, Colombia
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel fused pyrazolo[3,4-b]pyrazines 3 were prepared by assisted microwave cyclocondensation reaction
of ortho-aminonitrosopyrazoles 1 and cyclic b-diketones 2 in dimethylformamide. This protocol provides
a simple procedure for the synthesis of the title compounds with the advantages of easy work-up, mild
reaction conditions and good yields.
Received 27 March 2012
Revised 17 April 2012
Accepted 18 April 2012
Available online 25 April 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Pyrazolo[3,4-b]pyrazines
Aminonitrosopyrazoles
Cyclic b-diketones
Cyclocondensation
Microwave
Pyrazolo[3,4-b]pyrazines are an interesting variety of heterocy-
clic compounds of great importance. It has been reported that
some pyrazolopyrazine derivatives are used as bone metabolism
improvers, anti-inflammatory, anti-aggregation of blood platelets
and antitumoural agents.1,2
CN
NH2
H3C
NO
NH2
R
N
CN
Pyridine
Reflux
N
N
N
N
N
CN
On the other hand, focused microwave irradiation (MWI) is
emerging as a powerful tool to simplify and improve classic organ-
ic reactions, because it often leads to higher yields, cleaner and
shorter reactions with precise control of its parameters.3
In general, aromatic nitroso derivatives react with compounds
containing activated methylene groups. This procedure is known
as the Ehrlich–Sachs reaction,4 and has been used to prepare fused
pyrazolo[3,4-b]pyrazines from malonodinitrile as shown in Scheme
1.1a
Acyclic and cyclic 1,3-dicarbonyl compounds constitute impor-
tant synthetic precursors, which act either as nucleophilic or
electrophilic species according to a large variety of synthetic
transformations.5
Due to our interest in the development of synthetic strategies to
obtain new functionalized heterocycles,6 we have concentrated our
recent efforts in the preparation of bioactive nitrogen-containing
heterocycles. As mentioned previously, the pyrazolo[3,4-b]pyra-
zines present interesting properties, that have led us to focus this
research on the development of derivatives of this system through
the reaction of cyclic 1,3-dicarbonyl compounds with the title
heterocyclic nitrosoamines.5
Scheme 1. Synthesis of pyrazolopyrazines.1a
As an extension of the Ehrlich–Sachs reaction, we are reporting
here cyclocondensation reaction induced by focused microwave
irradiation of ortho-aminonitrosopyrazoles 1 and cyclic b-dike-
tones 2 to obtain the pyrazolo[3,4-b]pyrazine derivatives 3.
In our initial study, various conditions, including solvents, tem-
perature and microwave irradiation power, were tested, in order to
find out the best conditions for the synthesis of 3a from the nitros-
oamine 1 (R = CH3 and R0 = H) and dimedone 2a as a model reac-
tion. When pyridine was employed in the model reaction as a
solvent at room temperature, no product was observed (Table 1,
entry 1). This same reaction in pyridine using a reflux system affor-
ded the product 3a but after a long reaction time (10 h, entry 2).
When the reaction was conducted in DMF under reflux, the desired
product 3a was obtained also in low yield (40%, entry 4). It should
be noted that the desired product 3a was obtained in high yield
(85%, entry 5), when the reaction was conducted under microwave
irradiation in DMF. Increasing the power or temperature in the
microwave reactor did not improve the reaction efficiency, even
⇑
Corresponding author. Fax: +57 2 3392440.
E-mail address: jaiquir@univalle.edu.co (J. Quiroga).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.083

3182
J. Quiroga et al. / Tetrahedron Letters 53 (2012) 3181–3187
Table 1
in some cases complex reaction mixtures were obtained and diffi-
cult to purify (TLC control) (entries 9, 10).
A
study of the reaction of 5-amino-3-methyl-4-nitroso-1-phenylpyrazole 1 with
dimedone 2a
In a general experimental procedure (Table 1, entry 5), equimo-
lar amounts of starting compounds 1 and 2 in dimethylformamide
were exposed to MWI during 4–18 min. It was used as a focused
microwave reactor (CEM Discover TM) at 80 °C, power 100 W,
10 psi with this procedure the compounds 3 were isolated in a
range of moderate to good yields, after purification by simple
recrystallization from dimethylformamide or ethanol (Scheme 2,
Table 1).7 All the new compounds 3 present fluorescent properties.
As shown in Table 2, this protocol can be applied not only to cyclo-
hexanodione derivatives, but also to several cyclic 1,3-dicarbonyl
compounds.
Entry
Solvent
Conditions
Time (min)
Yield (%)
a
1
2
3
4
5
6
7
8
9
Pyridine
Pyridine
AcOH
DMF
DMF
DMF
DMF
DMF
DMF
DMF
RT
Reflux
Reflux
Reflux
MW (80 °C, 100 W)
MW (80 °C, 150 W)
MW (100 °C, 150 W)
MW (150 °C, 150 W)
MW (180 °C, 200 W)
MW (200 °C, 200 W)
60
600
60
480
9
8
8
6
5
—
35
a
—
40
85
70
70
60
45
40
10
5
a
There was no reaction.
The structures of all new compounds were determined by ana-
lytical techniques: 1D and 2D NMR-spectroscopy, MS and elemen-
tal analysis. The analytical data are agreed with the proposed
structures.
A possible mechanism for the described cyclocondensation
reaction is outlined in Scheme 3. Presumably, the reaction starts
with a nucleophilic addition of the activated methylene to the ni-
troso group of the pyrazole forming the intermediate imine 5. This
addition is favored due to the higher nucleophilicity that presents
the activated methylene in contrast to the amino group of the pyr-
azole.8 Subsequently, the intermediate 5 cyclizes via remaining
NH2 group with the terminal side chain carbonyl group (C@O) to
form final pyrazolopyrazine 3.
In summary, the described microwave-assisted synthesis is a
simple and practical method for the preparation of novel pyrazol-
o[3,4-b]pyrazines with the advantages of easy work-up, mild reac-
tion conditions and good yields. The biological and fluorescent
O
O
R
NO
R
N
N
DMF
MW
N
N
NH2
N
1
N
O
80 ºC, 100 W
2
R`
R`
3
R = CH3, (CH3)3C R´ = H, 4-Cl, 4-Br, 4-CN
Scheme 2. Synthesis of fused pyrazolo[3,4-b]pyrazine derivates 3.
Table 2
New fused pyrazolo[3,4-b]pyrazines 3
Entry
b-diketone
Product
Time (min)
Mp (°C)
Yield (%)
O
O
N
H3C
N
CH3
CH3
CH3
CH3
O
3a
8
188–190
85
N
N
N
N
O
O
N
H3C
O
N
3b
9
169–171
74
N
O
O
NH
NH
N
H3C
O
O
N
H
O
N
H
N
3c
10
>350
64
N

J. Quiroga et al. / Tetrahedron Letters 53 (2012) 3181–3187
3183
Table 2 (continued)
Entry
b-diketone
Product
Time (min)
Mp (°C)
Yield (%)
O
O
N
H3C
N
3d
4
228–230
65
N
O
N
O
O
O
N
H3C
H3C
H3C
H3C
O
O
N
N
N
N
3e
10
258–260
68
N
N
N
N
O
O
NH
N
N
N
O
N
H
3f
6
>350
65
N
N
N
O
O
O
O
3g
8
257–259
63
O
O
O
CH3
CH3
CH3
CH3
O
N
3h
8
204–206
61
Cl
O
O
NH
NH
N
H3C
O
O
N
H
O
N
N
H
N
N
3i
8
>350
50
Cl
(continued on next page)

3184
J. Quiroga et al. / Tetrahedron Letters 53 (2012) 3181–3187
Table 2 (continued)
Entry
b-diketone
Product
Time (min)
Mp (°C)
Yield (%)
O
O
N
H3C
N
N
N
O
3j
6
274–276
49
Cl
O
O
O
N
H3C
N
O
O
N
N
3k
10
304–306
65
Cl
O
O
NH
N
H3C
N
O
N
H
N
N
3l
14
>350
46
Cl
O
O
O
N
H3C
N
O
N
N
3m
12
251–253
52
O
Cl
O
O
N
H3C
N
CH3
CH3
CH3
CH3
O
N
N
3n
6
193–195
61
Br

J. Quiroga et al. / Tetrahedron Letters 53 (2012) 3181–3187
3185
Table 2 (continued)
Entry
b-diketone
Product
Time (min)
Mp (°C)
Yield (%)
O
O
NH
NH
N
H3C
N
O
O
N
H
O
N
H
N
N
3o
16
293–295
43
Br
O
O
O
O
N
H3C
N
O
N
N
3p
8
315–316
55
Br
O
O
O
O
NH
N
N
N
H3C
H3C
H3C
O
N
H
N
N
N
N
N
N
N
3q
3r
3s
14
12
8
>350
51
Br
O
O
O
N
268–270
45
O
Br
O
O
O
O
N
323–325
42
CN
(continued on next page)

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J. Quiroga et al. / Tetrahedron Letters 53 (2012) 3181–3187
Table 2 (continued)
Entry
b-diketone
Product
Time (min)
Mp (°C)
Yield (%)
O
O
NH
N
H3C
N
O
N
H
N
N
3t
10
>350
40
CN
N
O
O
O
N
H3C
O
N
N
3u
8
298–300
48
O
CN
O
O
O
O
O
CH3
CH3
N
H3C
H3C
H3C
H3C
CH3
CH3
CH3
CH3
O
N
3v
3w
3x
3y
13
18
15
14
166–168
51
50
51
41
N
N
N
N
N
O
CH3
CH3
NH
NH
N
N
N
O
O
N
H
O
N
H
N
>350
N
O
O
CH3
CH3
O
O
N
264–265
N
O
CH3
CH3
NH
O
N
H
N
>350
N

J. Quiroga et al. / Tetrahedron Letters 53 (2012) 3181–3187
3187
H
O
O
R
O
O
R
N=O
NH2
N
OH
N
N
NH2
4
N
HO
O
N
2
R´
O
R´
1
-H2O
O
3
O
R
N
R
R
N
N
-H2O
O
N
N
N
N
N
H
NH2
N
N
N
OH
6
5
R´
R´
R´
Scheme 3. Possible mechanism for the formation of fused pyrazolopyrazines 3.
M.; Cobo, J. Tetrahedron Lett. 2010, 51, 4717–4719; (f) Quiroga, J.; Portilla, J.;
Abonía, R.; Insuasty, B.; Nogueras, M.; Cobo, J. Tetrahedron Lett. 2008, 49, 6254–
6256.
properties of the new compounds obtained in this research are un-
der investigation.
6. (a) Quiroga, J.; Trilleras, J.; Insuasty, B.; Abonía, R.; Nogueras, M.; Cobo, J.
Tetrahedron Lett. 2008, 49, 2689–2691; (b) Quiroga, J.; Trilleras, J.; Insuasty, B.;
Abonía, R.; Nogueras, M.; Marchal, A.; Cobo, J. Tetrahedron Lett. 2008, 49, 3257–
3259; (c) Quiroga, J.; Insuasty, B.; Insuasty, H.; Abonía, R.; Ortíz, A. J.; Sánchez,
A.; Nogueras, M. J. Heterocycl. Chem. 2001, 38, 339–341; (d) Quiroga, J.; Hormaza,
A.; Insuasty, B.; Ortíz, A. J.; Sánchez, A.; Nogueras, M. J. Heterocycl. Chem. 1998,
35, 231–233.
Acknowledgement
Authors wish to thank the COLCIENCIAS and Universidad del
Valle for financial support.
7. General procedure for the preparation of fused pyrazolo[3,4-b]pyrazines 3:
Microwave experiment was carried out using a focused microwave reactor
References and notes
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filtration, washed with ethanol, dried in air and recrystallized from
A
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dimethylformamide.
Data
for
3,7,7-trimethyl-1-phenyl-7,8-dihydro-1H-
pyrazolo[3,4-b]quinoxalin-5(6H)-one 3a: Yellow solid, yield 85%, 188–190 °C.
1H NMR (400 MHz CDCl3) d: 1.20 (s, 6H, CH3-7), 2.81 (s, 2H, CH2-8), 2.82 (s, 3H,
CH3-3), 3.30 (s, 2H, CH2-6), 7.35 (t, 1H, Hp), 7.55 (t, 2H, Hm), 8.29 (d, 2H, Ho). 13
C
NMR (100 MHz CDCl3) d: 11.8 (CH3-3), 28.3 (CH3-7), 32.8 (C-7), 47.2 (CH2-8),
53.2 (CH2-6), 120.4 (Co), 126.4 (Cp), 129.3 (Cm), 135.4 (C-3a), 138.6 (Ci), 139.2
(C-4a), 143.1 (C-9a), 146.3 (C-3), 157.3 (C-8a), 195.9 (C-5). EI EM: m/z: 306 (M+,
100). Anal. Calcd for C18H18N4O: C, 70.57; H, 5.92; N, 18.29; Found: C, 70.79; H,
5.98; N, 18.16.
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