Microwave-assisted synthesis of pyrazolo[3,4-d]pyrimidines from 2-amino-4,6-dichloropyrimidine-5-carbaldehyde under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2008.03.090

The microwave-induced synthesis of pyrazolo[3,4-d]pyrimidines 4 in the reaction of N⁴-substituted-2,4-diamino-6-chloro-5-carbaldehydes 3 with hydrazine is described here. Precursors 3 have been prepared by the mono-amination of 2-amino-4,6-dich

Full text of DOI:10.1016/j.tetlet.2008.03.090

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3257–3259
Microwave-assisted synthesis of pyrazolo[3,4-d]pyrimidines
from 2-amino-4,6-dichloropyrimidine-5-carbaldehyde under
solvent-free conditions
a,
a
a
a
*
´
Jairo Quiroga , Jorge Trilleras , Braulio Insuasty , Rodrigo Abonıa ,
Manuel Nogueras b,*, Antonio Marchal b, Justo Cobo b
a Heterocyclic Compounds Research Group, Department of Chemistry, Universidad del Valle, A. A. 25360 Cali, Colombia
b Department of Inorganic and Organic Chemistry, Universidad de Jae´n, 23071 Jae´n, Spain
Received 31 January 2008; revised 12 March 2008; accepted 18 March 2008
Available online 23 March 2008
Abstract
The microwave-induced synthesis of pyrazolo[3,4-d]pyrimidines 4 in the reaction of N4-substituted-2,4-diamino-6-chloro-5-carbalde-
hydes 3 with hydrazine is described here. Precursors 3 have been prepared by the mono-amination of 2-amino-4,6-dichloropyrimidine-5-
carbaldehyde 2 with aliphatic and aromatic amines. The reaction times with primary amines were relatively shorter than for secondary
amines.
Ó 2008 Published by Elsevier Ltd.
Keywords: Formylation; Vilsmeier–Haack reaction
The structural diversity and biological importance of
pyrimidines have made them attractive targets for synthesis
over many years. The pyrimidine is a widespread hetero-
cyclic moiety, which is present in numerous natural prod-
ucts as well as synthetic pharmacophores with biological
activities.1 Substituted pyrimidines, particularly with
amino-groups at 2 and 4 positions, are known pharmaco-
phores in several structure-based drug design approaches
in medicinal chemistry.2 The 5-formylpyrimidines can be
used as precursor in the synthesis of fused pyrimidine sys-
tems, among them we highlight the pyrazolo[3,4-d]pyrimi-
dines, which are formed in several steps from a suitable
pyrazole, or less frequently from a pyrimidine.3 Pyrazolo-
[3,4-d]pyrimidines are a class of heterocyclic compounds
with very important biological properties.4
On the other hand, it has become widely accepted that
many classical reactions under microwave irradiation per-
form better than reactions by conventional heating.5,6
The microwave irradiation can be used to carry out a wide
range of reactions in short times and with high yield and
regioselectivity, without the need for solvents.7 In the
course of our research field aimed at the preparation of bio-
active nitrogen-containing heterocycles, we addressed the
synthesis of pyrazolo[3,4-d]pyrimidines. In this letter, we
describe a versatile synthesis of N4-substituted-4,6-diamin-
opyrazolo[3,4-d]pyrimidines 4 using microwave irradiation
in the absence of solvent from N4-substituted-2,4-diamino-
6-chloropyrimidine-5-carbaldehydes 3 in the reaction with
hydrazine hydrate with good yields (Scheme 1 and Table
1). It is interesting to note that when this same reaction
was carried out by conventional heating of aldehydes 3
with hydrazine hydrate, reactions preceded rather similarly
rendering products 4 in equal yields. The only difference
between those methods is that by microwave irradiation
the reaction time is much shorter than by heating, 1 versus
30 min, respectively.8
*
Corresponding authors. Fax: +57
618907111 (M.N.).
2 33392440 (J.Q.); fax: +34
E-mail addresses: jaiquir@univalle.edu.co (J. Quiroga), mmontiel@
ujaen.es (M. Nogueras).
0040-4039/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2008.03.090

3258
J. Quiroga et al. / Tetrahedron Letters 49 (2008) 3257–3259
OH
N
Cl
Cl
HN
N
Ethanol, TEA
HNR1R2
reflux
method A or
method B
POCl3 / DMF
N
N
N
N
O
O
H2N
OH
H2N
N
Cl
H2N
N
NR1R2
H2N
N
NR1R2
1
2
3
4
Scheme 1.
Table 1
Products of mono-amination of 4,6-dichloropyrimidine-5-carbaldehyde 3 and preparation of 4-substituted-pyrazolo[3,4-d]pyrimidines 4
Entry
Amine
Compound 3
Compound 4
Mp (°C) (a)
Yield (%)
Mp (°C)
Yieldb (%)
1
2
3
4
5
6
7
8
9
N-Methylaniline
N-Ethylaniline
4-Methoxy-N-methylaniline
Aniline
p-Toluidine
3-Chloroaniline
>180 dec
170–172 (166–169)
163–165
209–211 (205–207)
202–204
233–235
226–228
193–195
181–183
183–185
176–178
>300 dec
>250 dec
179–181
165–167
114–116
160–162
169–171 (168–170)
114–116
160–162
202–204
>185 dec
131–133 (134–137)
189–191
92–94
134–136
194–196
173–175
94
96
80
80
75
85
80
93
80
80
80
70
70
70
70
70
80
40
70
40
60
95
70
80
60
60
80
71
54
81
72
313–315
275–277
205–207
296–298
271–273
289–291
296–298
248–250
222–224
265–267
270–272
>300 dec
>300 dec
>250 dec
257–259
198–200
282–284
221–223
198–200
234–236
233–235
>300 dec
259–261
>300
70
70
73
70
93
60
60
66
70
80
60
70
80
60
80
70
80
90
70
50
77
70
40
50
80
50
90
70
50
87
60
4-Chloroaniline
4-Methoxyaniline
2-Methoxy-N-methylaniline
2-Methyl-N-methylaniline
N-Methyl-p-toluidine
4-Aminophenol
10
11
12
13
14
15
16
17
18
19
21
22
23
24
25
26
27
28
29
30
31
32
a
4-Aminobenzoic acid
Benzylamine
N-Phenylbenzylamine
N-Ethylbenzylamine
3,4-Dimethoxybenzylamine
N-Methylbenzylamine
N-Ethylbenzylamine
Dibenzylamine
2-(1H-Pyrrol-1-yl)aniline
Indoline
Diethylamine
Dimethylamine
Dodecylamine
Cyclohexylamine
N-Methylcyclohexylamine
Piperidine
139–141
267–269
255–257
242–244
287–289
228–230
250–252
Pyrrolidine
Morpholine
2-(Piperazin-1-yl)ethanol
178–180 (181–184)
176–178 (173–174)
176–178
Mp reported in the literature.9
The yields reported were obtained by both methods.
b
4,6-Dichloropyrimidine-5-carbaldehyde 2 has been used
with 2-amino-4,6-dichloropyrimidine-5-carbaldehyde 2 to
give the mono-substituted compounds 3 in good yields,
which is controlled with equimolar ratio of reagent.
If instead of equimolar ratio, the amination of 2-amino-
4,6-dichloropyrimidine-5-carbaldehyde 2 was carried out in
the presence of a double molar ratio of amine and TEA
with respect to aldehyde 2, the disubstitution product 5
was obtained (Scheme 2).11,12
The structure of all new compounds was determined on
the basis of their analytical and 1D and 2D-NMR spectral
data mainly, HR-MS, which are in agreement with their
proposed structure. Single crystal X-ray diffraction
analysis of compound 4 (entry 1, R1 = C6H5, R2 = CH3)
and 5 (R1 = H3CC6H4, R2 = CH3) was used to corroborate
the postulated structures.12
as a functional starting material for the synthesis of
N4-substituted-2,4-diamino-6-chloropyrimidine-5-carbalde-
hydes, and due to the highly electron-deficient nature of the
pyrimidine ring the nucleophilic aromatic substitution
(SNAr) allows us to introduce the amino group of different
structures developing synthetic routes for the preparation
of various 5-pyrimidinecarbaldehydes 3.9 Accordingly, we
carried out the reaction of equimolar amounts of aldehyde
2 with a variety of amines, aliphatic, aromatic and hetero-
cyclic, in a basic medium (triethylamine, TEA) under etha-
nol reflux (Scheme 1 and Table 1).10
As it can be seen from Table 1 all types of amines,
including aliphatics, cyclic and alicyclic amines, aromatic,
heteroaromatic and benzylic amines reacted readily well

J. Quiroga et al. / Tetrahedron Letters 49 (2008) 3257–3259
3259
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NR1R2
Cl
HNR1R2
N
O
N
O
2 TEA, Ethanol
reflux 1 h
H2N
N
NR1R2
H2N
N
Cl
2
5
Scheme 2.
We have prepared a variety of N4-substituted-2,4-di-
amino-6-chloropyrimidine-5-carbaldehydes by mono-
amination with a variety of amines, when the nucleophilic
mono-substitution is controlled with the molar ratio of
reagent. These compounds are useful intermediates in the
preparation of fused pyrimidine derivatives, such as
pyrazolo[3,4-d]pyrimidines, which can be prepared also
under microwave irradiation in the absence of solvent.
7. (a) Kappe, C. O. Angew. Chem. 2004, 43, 6250–6284; (b) Varma, R. S.
Pure Appl. Chem. 2001, 73, 193–198.
8. General procedure for the reaction of 2-amino-4-amine-6-chloropyrim-
idine-5-carbaldehydes with hydrazine monohydrate. Microwave method:
A mixture of compound (3) (0.2 mmol) and an excess of hydrazine
monohydrate (0.5 mL) was subjected to microwave irradiation in the
absence of solvent (maximum power 300 W during 1 min at a
controlled temperature of 373 K) using a focused microwave reactor
(CEM Discover). The solid products were collected by filtration and
washed with ethanol and diethyl ether to give compound (4). Data for
N4-methyl-N4-phenyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine
4
(entry 1, R1 = C6H5, R2 = CH3), white crystalline solid, yield 70%,
mp 313–315 °C. 1H 400 MHz, DMSO-d6, d: 3.44 (s, 3H, CH3), 5.61 (s,
1H, 3-H), 6.14 (s, 2H, NH2), 7.55–7.38 (m, 5H, Haromatics), 12.41 (s,
1H, NH). 13C 100 MHz, DMSO-d6, rt, d: 38.0 (CH3), 95.2 (C-3a),
128.0 (Cp), 128.3 (Cm), 130.0 (Co), 132.8 (CH), 145.1 (Ci), 157.3 (C-4),
158.0 (C-7a), 161.7 (C-6). HR-MS calcd for C12H12N6 240.1123,
found 240.1122. Anal. Calcd for C12H12N6: C, 59.99; H, 5.03; N,
34.98. Found: C, 60.87; H, 5.74; N, 36.07.
Conventional method: A mixture of compound 3 (0.2 mmol) and an
excess of hydrazine monohydrate (0.5 mL) in ethanol (5 mL) was
heated under reflux for 30 min, then allowed to cool. The solid
product was collected and washed with ethanol and diethyl ether to
give the compound (4).
Acknowledgements
´
´
The authors thank ‘Servicios Tecnicos de Investigacion
of Universidad de Jaen’ and the staff for data collection,
´
´
´
and the Consejerıa de Innovacion, Ciencia y Empresa
´
´
(Junta de Andalucıa, Spain), the Universidad de Jaen and
Universidad del Valle for financial support. J.T. thanks
Colciencias for supporting a research visit to the Universi-
´
dad de Jaen, and Fabio Zuluaga for reviewing this
manuscript.
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P. J. Org. Chem. 1992, 57, 5757–5761; (c) Seela, F.; Sterker, H. Helv.
Chim. Acta 1986, 69, 1602–1613.
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