A facile one step synthesis of 1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7- ones

Article abstract of DOI:10.1002/jhet.5570420502

A general synthetic approach to pyrazolo[4,3-d]pyrimidines is reported. Aldehydes, arylideneanilines, carboxylic acids and orthoesters are used as one-carbon units for bridging the two amino functions of 4-amino-1-alkyl-3- propylpyrazole-5-carboxamides.

Full text of DOI:10.1002/jhet.5570420502

Jul-Aug 2005
751
A Facile One Step Synthesis of 1,6 -Dihydro-7H-pyrazolo[4,3-d]-
pyrimidin-7-ones
Nalla Ram Reddy, Ghanta Mahesh Reddy, Battu Saida Reddy, Padi Pratap Reddy*
†
Department of Chemistry, Osmania University, Hyderabad-500 007, India
Fax: +91 40 23095438; E-mail: reddyppou@yahoo.co.in
†
Present Address: Research and Development, Dr. Reddys Laboratories Ltd., API, Unit-IV, Plot No. 9/A,
Phase-III, IDA, Jeedimetla, Hyderabad-500 055, India
Received July 26, 2004
A general synthetic approach to pyrazolo[4,3-d]pyrimidines is reported. Aldehydes, arylideneanilines,
carboxylic acids and orthoesters are used as one-carbon units for bridging the two amino functions of
4-amino-1-alkyl-3-propylpyrazole-5-carboxamides.
J. Heterocyclic Chem., 42, 751 (2005).
in acetic acid containing a catalytic amount of p-toluene-
sulfonic acid. Tetrahydropyrazolo[4,3-d]pyrimidin-7-one
derivative 7 was obtained when 1a was reacted with
4-N,N-dimethylamino benzaldehyde in acetic acid at
ambient temperature. The intermediacy of 7 in the forma-
tion of 6a was proved by the independent conversion of 7
into 6a in refluxing acetic acid in the presence of p-tolue-
nesulfonic acid.
The versatility of arylideneanilines as aldehyde source-
cum-dehydrogenating agents in heterocyclisation reactions
was earlier demonstrated in benzimidazole [14,15] and
quinazolinone [16,17] chemistry. Therefore, we surmised
Pyrazolo[4,3-d]pyrimidine derivatives [1-10] are the
structural analogues of purines. Their excellent adenosine
receptor antagonist activity [9] and other useful pharmaco-
logical properties such as vasodilator [10,11] and antibac-
terial [12] activities made them interesting targets for syn-
thesis.
Herein, we report a facile general approach for the syn-
thesis of pyrazolo[4,3-d]pyrimidin-7-one derivatives (6a-l)
from 4-amino-1-methyl (or ethyl)-3-propylpyrazole-5-car-
boxamide 1a [13] or 11 using one-carbon electrophilic
sources. Pyrazolo[4,3-d]pyrimidin-7-ones (6a-h) were
obtained by refluxing 1a with appropriate aldehydes 2a-h
Scheme 1

752
N. R. Reddy, G. M. Reddy, B. S. Reddy, P. P. Reddy
Vol. 42
Table 1
Yield and Melting Point of 1-Alkyl-5-aryl-3-propyl-6,7-dihydro
-1H-pyrazolo[4,3-d]pyrimidin-7-ones (6a-l)
Entry
Compd. No.
Yield (%)
m.p (°C)
Method-A
Method-B
Method-C
Method-D
1
2
3
4
5
6
7
8
6a
6b
6c [18]
6d [18]
6e [18,19]
6f
60
58
61
75
57
68
70
55
--
55
60
52
59
53
66
65
52
--
--
51
48
66
51
62
63
--
--
--
--
--
--
--
--
--
--
--
--
--
83
83
78
77
245
240
242
239
227
210
212
148
226
176
214
205
6g
6h [20]
6i [21]
6j [22]
6k [23]
6l
9
10
11
12
--
--
--
--
--
--
All the compounds were purified by recrystallization from ethyl acetate/n-hexane (1:1); Method-A: From the
reaction of 1a with aldehyde in acetic acid under reflux condition; Method-B: From the reaction of 1a with aryli-
deneaniline (1:2) in acetic acid at room temperature; Method-C: From the reaction of 1a with aromatic carboxylic
acid in PPA; Method-D: From the reaction of 1a or 1l with orthoesters.
Polman digital melting point apparatus (model no MP 96) and
reported in degree centigrade. Ultraviolet spectra were recorded
in MeOH on Shimadzu 1601 PC model UV visible spectropho-
tometer and the absorption maxima are presented in nm. Infrared
spectra were recorded in KBr pellets on Shimadzu 435 instru-
that, arylideneaniline may as well react with 1a and pro-
vide 6 in one step. Thus 1:2 molar reaction of 1a and aryli-
deneanilines 3a-h in acetic acid at ambient temperature
directly afforded pyrazolo[4,3-d]pyrimidin-7-ones (6a-h).
On the other hand, an equimolar reaction of 1a and aryli-
deneaniline under similar experimental conditions pro-
vided 7. Obviously, the second mole of arylideneaniline
acted as a dehydrating agent.
Aromatic carboxylic acids 4b-g also afforded the corre-
sponding pyrazolo[4,3-d]pyrimidin-7-one derivatives 6b-g
in one step on heating with 1a in polyphosphoric acid
(PPA), albeit in moderate yields. Triethyl orthoesters 5i
and 5k directly provided the pyrazolo[4,3-d]pyrimidin-7-
one derivatives 6i-l in good yields on reacting with pyra-
zole carboxamides 1a / 1l in refluxing xylene.
-1
ment. The absorptions are quoted in 2.5 cm . Proton magnetic
resonance spectra were recorded on Varian Gemini (200 MHz)
spectrometer with TMS as internal standard. Chemical shift val-
ues are given in δ scale. The solvent in which the NMR spectrum
was recorded is indicated at the appropriate places. Mass spectra
were recorded on VG-Micro Mass 70-70H instrument with direct
inlet probe.
Preparation of 5-Aryl-1-methy-l,6-dihydro-7H-pyrazolo[4,3-d]-
pyrimidin-7-ones (6a-h).
General Procedure A.
4-Amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide 1a
(0.01 mol) and the appropriate aldehydes 2a-h (0.01 mol) were
dissolved in acetic acid (20 mL) and catalytic amount of p-tolu-
ensulfonic acid (10 mg) was added. The reaction mixture was
refluxed for 6 h, cooled to room temperature and diluted with
water (60 mL). The crude solid which separated was collected by
filtration, dried, and recrystallised from an appropriate solvent to
afford 5-aryl-1-methyl-1,6-dihydro-7H-pyrazolo[4,3-d] pyrim-
idin-7-ones 6a-h in good yields.
IR spectra of compounds 6a-h showed characteristic
amide NH and carbonyl absorptions at ~3200 and ~1680
-1
1
cm , respectively. H-NMR spectra of these compounds
are characterized by the presence of signals due to n-
propyl and N-methyl groups of pyrazole moiety in the up
field region.
In conclusion, we have developed a facile general
method for the synthesis of pyrazolo[4,3-d]pyrimidin-7-
one derivatives from 4-amino-1-alkyl-3-propyl-1H-pyra-
zole-5-carboxamides by inserting a one-carbon unit
derived from suitable aldehydes, arylideneanilines, car-
boxylic acids and orthoesters. Readily accessible starting
materials and simple reaction conditions render this syn-
thesis procedure attractive.
General Procedure B.
4-Amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide 1a
(0.01 mol) and the appropriate arylideneaniline 3a-h (0.02 mol)
in acetic acid (20 mL) were stirred at room temperature for 4 h.
The reaction mixture was diluted with water (100 mL) and the
solid that separated was collected by filtration, washed with n-
hexane (25 mL), dried and recrystallised from suitable solvent to
give the 5-aryl-1-methyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrim-
idin-7-ones 6a-h in good yields.
EXPERIMENTAL
General Procedure C.
All the melting points were determined in capillaries using
A mixture of 4-amino-1-methyl-3-propyl-1H-pyrazole-5-car-

Jul-Aug 2005
A Facile One Step Synthesis of 1,6 -Dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-ones
753

754
N. R. Reddy, G. M. Reddy, B. S. Reddy, P. P. Reddy
Vol. 42
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boxamide 1a (0.01 mol) the appropriate aromatic carboxylic acid
4b-g (0.01 mol) and polyphosphoric acid (PPA, 10 mL) was
heated at 85-90 °C for 2 h. The reaction mixture was poured onto
crushed ice (200 g). The separated crude product was collected
by filtration, washed with water, dried, and recrystallised from a
suitable solvent to afford 5-aryl-1-methyl-1,6-dihydro-7H-pyra-
zolo[4,3-d]pyrimidin-7-ones 6b-g in good yields.
General Procedure D.
A solution containing 4-amino-1-methyl (or ethyl)-3-propyl-
1H-pyrazole-5-carboxamide 1a or 1l (1 mmoles) and the appro-
priate triethyl orthoester 5i or 5k (1.5 mmoles) in xylene (20 mL),
was heated under reflux for 4 h. The reaction mixture was cooled
to room temperature and diluted with n-hexane (75 mL). The
crude product that separated was collected by filtration, washed
with n-hexane (10 mL) and recrystallised from suitable solvent to
give 5-methyl (or unsubstituted)-1-methyl (or ethyl)-1,6-dihy-
dro-7H-pyrazolo[4,3-d]pyrimidines 6i-l in good yields.
5-(4-Dimethylaminophenyl)-1-methyl-3-propyl-4,5,6,7-tetrahy-
dro-7H-pyrazolo[4,3-d]pyrimidin-7-one (7).
A solution containing 4-amino-3-propyl-1-methyl-1H-pyra-
zole-5-carboxamide 1l (0.01 moles) and 4-(dimethylamino) ben-
zaldehyde 2a (0.01 moles) in glacial acetic acid (10 mL) was
stirred at room temperature for 4 h. The reaction mixture was
cooled to room temperature and diluted with water (100 mL).
The separated crude product was collected by filtration, air-dried
and recrystallised from a 1:1 mixture of ethyl acetate and n-
+
hexane to give 7 in 71 % yield, m.p. 193 °C; MS: m/z. 313 (M );
1
IR (KBr): 1667 (C=O), 3155 (NH), 3305 (NH); H-NMR
(CDCl ): δ 1.0 (s, 3H, CH ), 1.7 (m, 2H, CH ), 2.7 (t, 2H, CH ),
3
3
2
2
3.08 (s, 6H, 2 x N-CH ), 4.2 (s, 3H, N-CH ), 5.6 (br s, 1H, NH),
3
3
6.75 (d, 2H, J=11.5 Hz, Ar-H), 7.65 (d, 2H, J=11.5 Hz, Ar-H),
8.4 (s, 1H, methane CH), 8.7 (br s, 1H, NH).
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