Studies on uracils: A facile one-pot synthesis of pyrazolo[3,4-d]pyrimidines

Article abstract of DOI:10.1002/jhet.5570380230

The reaction of 6-hydrazino uracils 1 and nitrones 2 result in an efficient one-pot synthesis of pyrazolo[3,4-d]pyrimidines 3 in excellent yields. The isolation of the by-product aniline from the reaction mixture supported the plausible mechanism for the formation of pyrazolo[3,4-d]pyrimidines.

Full text of DOI:10.1002/jhet.5570380230

Mar-Apr 2001
Studies on Uracils: A Facile One-pot
Synthesis of Pyrazolo[3,4-d]pyrimidines
P. J. Bhuyan, H. N. Borah, K. C. Lekhok and J. S. Sandhu*
491
Regional Research Laboratory, Jorhat 785006, Assam, India
Received August 7, 2000
The reaction of 6-hydrazino uracils 1 and nitrones 2 result in an efficient one-pot synthesis of
pyrazolo[3,4-d]pyrimidines 3 in excellent yields. The isolation of the by-product aniline from the reaction
mixture supported the plausible mechanism for the formation of pyrazolo[3,4-d]pyrimidines.
J. Heterocyclic Chem., 38, 491 (2001).
The importance of uracil and its annelated substrate is well
Our synthetic strategy utilising 6-hydrazinouracils 1
with nitrones 2 at room temperature afforded an
unprecedented one pot synthesis of pyrazolo[3,4-d]-
pyrimidines 3 in excellent yields.
recognised by synthetic [1] as well as biological [2] chemists.
Pyrazolo[3,4-d]pyrimidines are a class of annulated uracils of
special interest in medicinal chemistry [3], which have been
studied extensively as antitumor agents [4]. 4-(n-
Propylamino)-pyrazolo[3,4-d]pyrimidine has been examined
in clinical studies against disseminated tumors and human
leukemia [5]. Interestingly, the literature survey revealed only
few reports for the synthesis of pyrazolo[3,4-d]pyrimidines
the majority of which require drastic conditions and complex
synthetic pathways. As a part of our research programme on
uracils [6] we report here a very simple, mild and efficient
method for the synthesis of Pyrazolo[3,4-d]pyrimidines by
exploring the nucleophilic double bond of uracils.
A previous synthesis for pyrazolo[3,4-d]pyrimidine
reported by Yoneda et al. [7] involved the cycloaddition
of azahexatriene obtained from the reaction of arylalde-
hyde and 6-uracil hydrazone. One disadvantage of this
approach is the concomitant alkylation of the pyrazolo
moiety. Another synthesis reported by Maki et al. [8]
required the cycloaddition of arylhydrazones with
6-chloro-5-nitro uracils involving several steps.
Kanazawa et al. [9] synthesised pyrazolo[3,4-d]pyrim-
idines by the reaction of 6-arylidinehydrazinouracils with
N-bromosuccinimide (NBS) in acetic acid under refluxing
conditions, which yield triazino and pyridazinouracils in
addition to the pyrazolo[3,4-d]pyrimidines.
In a very simple experimental procedure equimolar
amount of 6-hydrazino uracil 1 and nitrone 2a were
stirred at room temperature for 12 hours (Scheme 1). The
product appeared as a thick precipitate which was
filtered, washed with a small amount of ethanol and
dried. The compound, obtained in 95% yield, was
recrystallised from ethanol. The structure was fully
characterised as 3a through spectral and elemental analy-
ses and found to be comparable in all respect to the
authentic sample. The eliminated by-product aniline 4
was isolated from the filtrate by evaporating the solvent
and passing the residue through a silica gel column using
chloroform-ethylacetate (4:1) as eluent. The structure
was confirmed from spectroscopic data and by
comparing with the authentic compound. The formation
of the by-product can be explained by the mechanism
shown. Similarly compounds 3b-f were synthesised and
structures confirmed from spectroscopic data and
elemental analyses. Melting points and mixed melting
points of compounds 3b-c are comparable with authentic
compounds. The reaction was extended to conjugated
nitrones and found to proceed smoothly in the presence
of the carbon carbon double bond, which remains intact

492
P. J. Bhuyan, H. N. Borah, K. C. Lekhok and J. S. Sandhu
Vol. 38
EXPERIMENTAL
Melting points were determined in open capillary tubes on a
Buchi apparatus and are uncorrected. The 90 MHz NMR spectra
were recorded on a JEOL EX 90A spectrometer with deuterio-
chloroform (CDCl ) or CDCl + trifluoroacetic acid (TFA) as
3
3
solvent and tetramethylsilane (TMS) as the internal standard.
Chemical shift values are recorded in δ units (ppm). The IR
spectra were recorded on a Perkin-Elmer 237B spectrometer as
KBr discs. Mass spectra were recorded on a INCOS-50 GC-MS
instrument. Elemental analyses were performed on a Hitachi 026
CHN analyser.
General Procedure for the Synthesis of Pyrazolo[3,4-d]pyrim-
idines 3.
A mixture of 0.170 g (1 mmol) of 6-hydrazino uracil 1a and
0.197 g (1 mmol) of nitrone 2a in 10 ml ethanol was stirred at
room temperature for 12 hours. The thick precipitate formed was
filtered, washed with a small amount of ethanol and dried. The
filtrate was evaporated under reduced pressure and the residue
was chromatographed in a silica gel column using chloroform-
ethylacetate (4:1) as eluent. The product isolated was identified
as aniline from the physicochemical data and by comparing with
authentic sample. Similarly, compound 3b-h were prepared and
the structures confirmed from spectroscopic data and elemental
analysis (Tables 1).
Table 1
Analytical Data: Calcd./Found
Compound Molecular
No.
Formula
C
H
N
3a
3b
3c
3d
3e
3f
C
C
H
N O
N O
4
60.93/60.85
58.73/58.70
57.79/57.70
53.66/53.80
59.50/59.41
51.73/51.79
63.82/63.75
62.68/62.60
4.72/4.65
4.93/4.98
3.79/3.75
4.09/4.05
4.16/4.22
3.47/3.39
4.96/4.90
4.47/4.40
21.86/21.75
19.57/19.40
19.31/19.25
22.75/22.63
23.13/23.02
24.13/24.08
19.85/19.90
20.89/20.85
13 12
4
2
3
H
14 14
C
H N O Cl
13 11 4 2
C
H N O
11 10 4
3
5,7-Dimethyl-3-phenyl-1,7-dihydropyrazolo[3,4-d]pyrimidine-
4,6-dione (3a)
C
H N O
12 10 4
2
C
H N O
8 4 3
10
The product 3a was obtained in 95% yield (0.243 g) and
3g
3h
C
C
H N O
15 14 4
2
2
recrystallised from ethanol mp. 257 °C (lit. mp. 256-257 °C [9]).
H
N O
4
14 12
1
Mixed mp. 257 °C. H NMR (deuteriochloroform + trifluoro-
acetic acid): δ 2.95 (s, 3H), 3.30 (s, 3H), 6.75-7.20 (m, 5H). IR
-1
+
3220, 1700 cm . MS 256 (M ).
in the products. Thus the reaction of 1 and 2e yielded 3g
and 3h in excellent yield. In each case the by-product
aniline was isolated as usual from the reaction mixture.
A reasonable mechanism for the formation of 3 can be
explained by an initial nucleophilic addition of 1 to 2 with
a proton shift followed by the formation of the imine [A],
which subsequently undergoes a nucleophilic attack by the
6-hydrazino group to give the intermediate dihydro-
pyrazolo[2,3-d]pyrimidine [B]. Elimination of an aniline
molecule affords the fully aromatised compound 3
(Scheme 2). The mechanism is consistent with the
observation that aniline 4, which was isolated from the
reaction mixture and fully characterised, is a by-product.
In conclusion, we have demonstrated a very simple,
mild and efficient method for the synthesis of pyrazolo-
[3,4-d]pyrimidines of biological importance in excellent
yields. Heteroannulation on the nucleophilic double bond
of uracils, which is an important field in view of great
variety of potential products [10], usually requires either
forcing conditions [7,11] or relatively longer and complex
synthetic pathways [8,12]. Our results delineated above
have demonstrated that heteroannulation on the double
bond of uracils is possible under mild condition using
suitable organic synthones such as nitrones.
3-(4-Methoxyphenyl)-5,7-dimethyl-1,7-dihydropyrazolo[3,4-d]-
pyrimidine-4,6-dione (3b).
1
Compound 3b was obtained in 95% yield, mp. 271 °C [9]; H
NMR (deuteriochloroform + trifluoroacetic acid): δ 2.95 (s, 3H),
3.30 (s, 3H), 3.80 (s, 3H), 6.75-7.20 (m, 4H). IR 3225, 1700
-1
+
cm ; MS 286 (M ).
3-(4-Chlorophenyl)-5,7-dimethyl-1,7-dihydropyrazolo[3,4-d]-
pyrimidine-4,6-dione (3c).
Compound 3c was obtained in 94% yield, mp. >300 °C [9];
1
H NMR (deuteriochloroform + trifluoroacetic acid): δ 2.95
(s, 3H), 3.30 (s, 3H), 6.75-7.20 (m, 4H). IR 3220, 1700 Cm-1,
MS 290 (M+).
3-(Furyl)-5,7-dimethyl-1,7-dihydropyrazolo[3,4-d]pyrimidine-
4,6-dione (3d).
1
Compound 3d was obtained in 85% yield, mp. 236 °C,
H
NMR (deuteriochloroform + trifluoroacetic acid): δ 3.00 (s, 3H),
3.45 (s, 3H), 6.35-6.65 (m, 2H), 7.25 (d, 1H, J=2.6). IR 3225,
-1
+
1705 cm , MS 246 (M ).
5-Methyl-3-phenyl-1,7-dihydropyrazolo[3,4-d]pyrimidine-4,6-
dione (3e).
1
Compound 3e was obtained in 96% yield, mp. 257 °C,
H
NMR (deuteriochloroform + trifluoroacetic acid): δ 2.95 (s, 3H),
-1
+
6.80-7.25 (m, 5H), IR 3250, 3125 cm , MS 242 (M ).

Mar-Apr 2001
Studies on Uracils: A Facile One-pot Synthesis of Pyrazolo[3,4-d]pyrimidines
493
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1
Compound 3f was obtained in 85% yield, mp. 243 °C;
H
NMR (deuteriochloroform + trifluoroacetic acid): δ 3.00 (s, 3H),
6.30-6.45 (m, 2H), 7.10 (d, 1H, J = 2.6). IR 3245, 3120, 1695
-1
+
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1
Compound 3g was obtained in 90% yield, mp. 251 °C;
H
NMR (deuteriochloroform + trifluoroacetic acid): δ 3.00 (s, 3H),
3.45 (s, 3H), 6.30 (d, 1H, J = 10.4), 6.75-7.20 (m, 5H), 7.85 (d,
-1
+
1H, J = 12.4). IR 3225, 1705 cm , MS 282 (M ).
cis-5-Methyl-3-(2-phenylethenyl)-1,7-dihydropyrazolo-
[3,4-d]pyrimidine-4,6-dione (3h).
1
Compound 3h was obtained in 90% yield, mp. 265 °C;
H
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6.30 (d, 1H, J = 12.6), 6.75-7.20 (m, 5H), 7.85 (d, 1H, J = 10.6).
-1
+
IR 3225, 1705 cm , MS 268 (M ).
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