Synthesis of pyrazolo[3,4-d]-4,5-dihydropyrimidin-6-ones

Article abstract of DOI:10.1016/j.tetlet.2014.01.131

A small library of hitherto unprepared pyrazolo[3,4-d]-4,5- dihydropyrimidin-6-ones was synthesized on a preparative scale. The synthesis starts with a substituted 5-aminopyrazole that reacts with an isocyanate to give the corresponding urea. The latter undergoes a chlorotrimethylsilane-promoted [5+1] cyclocondensation with an aldehyde yielding the title pyrazolo[3,4-d]-4,5- dihydropyrimidin-6-one. Both synthetic steps are high-yielding (74-94%). The intermediates and the target compounds were isolated by simple crystallization. Ketones with the exception of isatin do not react with the open-chain urea intermediates.

Full text of DOI:10.1016/j.tetlet.2014.01.131

Accepted Manuscript
Synthesis of pyrazolo[3,4-d]-4,5-dihydropyrimidin-6-ones
Sergey V. Ryabukhin, Dmitry S. Granat, Andrey S. Plaskon, Alexander
Shivanyuk, Oleg Lukin
PII:
S0040-4039(14)00187-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.01.131
TETL 44164
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
25 October 2013
10 January 2014
29 January 2014
Please cite this article as: Ryabukhin, S.V., Granat, D.S., Plaskon, A.S., Shivanyuk, A., Lukin, O., Synthesis of
pyrazolo[3,4-d]-4,5-dihydropyrimidin-6-ones, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.
2014.01.131
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Sergey V. Ryabukhin, Dmitry S. Granat, Andrey S. Plaskon, Alexander Shivanyuk, Oleg Lukin

1
Tetrahedron Letters
journal homepage: www.els evier.com
Synthesis of pyrazolo[3,4-d]-4,5-dihydropyrimidin-6-ones
Sergey V. Ryabukhina,b,∗, Dmitry S. Granatb, Andrey S. Plaskonb, Alexander Shivanyuka, Oleg Lukinc
a The Institute of High Technologies, Kiev National Taras Shevchenko University, Glushkov St., Building 5, Kiev 01033, Ukraine
b Department of Chemistry, Kiev National Taras Shevchenko University, Volodymyrska St. 64, Kiev 01033, Ukraine
c Curplyx Drs, JSC Macrochem, Lunacharsky St. 4, 7th Floor, Kiev 02002, Ukraine
ARTICLE INFO
ABSTRACT
Article history:
Received
A
small library of hitherto unprepared pyrazolo[3,4-d]-4,5-dihydropyrimidin-6-ones was
synthesized on a preparative scale. The synthesis starts with a substituted 5-aminopyrazole that
reacts with an isocyanate to give the corresponding urea. The latter undergoes
Received in revised form
Accepted
a
chlorotrimethylsilane-promoted [5+1] cyclocondensation with an aldehyde yielding the title
pyrazolo[3,4-d]-4,5-dihydropyrimidin-6-one. Both synthetic steps are high-yielding (74–94%).
The intermediates and the target compounds were isolated by simple crystallization. Ketones
with the exception of isatin do not react with the open-chain urea intermediates.
Available online
Keywords:
Aldehydes
2009 Elsevier Ltd. All rights reserved.
Aminopyrazoles
Dihydropyrimidines
Ureas
Chlorotrimethylsilane
The pyrazolo[3,4-d]pyrimidine moiety is found in naturally
occurring nucleosides possessing significant antitumor activity
(e.g., formycin A and B)1 and some synthetic drugs.2 Another
important aspect of the pyrazolo[3,4-d]pyrimidine unit is its close
structural similarity to isomeric imidazolo[3,4-d]pyrimidine
(purine), which is the central framework of nucleic acid bases
and numerous other natural products and synthetic drugs.3 In
connection with this, the development of synthetic methods for
the preparation of pyrazolo[3,4-d]pyrimidine analogs with
programmed substitution patterns is of significance for medicinal
chemistry and drug discovery. The most frequently utilized
synthetic route to the pyrazolo[3,4-d]pyrimidine ring system is a
[5+1] cyclocondensation of difunctionalized pyrazoles with a
carbonyl compound.4 For example, a few bioactive pyrazolo[3,4-
d]pyrimidine derivatives were prepared through the
cyclocondensation of 4-carboxamido-5-aminopyrazole with
either formamide5 or urea.6 We have previously reported a high-
throughput
d]dihydropyrimidines through the reaction of 5-aminopyrazoles
with 2-haloazines or 2-haloazoles followed by
synthesis
of
extended
pyrazolo[3,4-
chlorotrimethylsilane-promoted [5+1] cyclocondensation with
aldehydes.7 The high yields of the latter synthesis combined with
the ease of availability of the reagents prompted us to further
explore the applicability of the chlorotrimethylsilane-promoted
cyclocondensation for the construction of previously
unobtainable pyrazolo[3,4-d]pyrimidine derived species.
Scheme 1. The preparation of open-chain urea intermediates
3. Reagents and conditions: 5-aminopyrazole, isocyanate,
MeCN, 60 °C.
———
∗ Corresponding author. Tel.: +380506424763; fax: +380506424763; e-mail: s.v.ryabukhin@gmail.com

2
Tetrahedron
In this communication we describe an efficient synthesis of
observations along with mass spectrometric data prove
unambiguously the formation of the bicyclic structures 5. Unlike
the reaction of 3 with aldehydes (Scheme 2), ketones, with the
exception of isatin, failed to react with ureas 3. As shown in
Scheme 3, isatin (6) reacts with ureas 3a,b,e to give 5',7'-
dihydrospiroindoline-3,4'-pyrazolo[3,4-d]pyrimidine-2,6'-diones
7 in 82-87% yield.
the first substituted pyrazolo[3,4-d]-4,5-dihydropyrimidin-6-ones
from commercially available 5-aminopyrazoles, isocyanates, and
aldehydes. The synthesis consists of two steps that are presented
in Schemes 1 and 2. In the first step (Scheme 1), open-chain
ureas 3 were prepared in yields of 76-88% through the reaction of
5-aminopyrazoles 1 with alkyl- or aryl-isocyanates 2.
In conclusion, the described two-step procedure readily gives
formerly unknown pyrazolo[3,4-d]-4,5-dihydropyrimidin-6-ones
5 which are isosteres of purine. Both synthetic steps proceed with
high yields; the purification of the products consists of simple
crystallization. The pyrazolo[3,4-d]-4,5-dihydropyrimidin-6-one
scaffold has four variation points that can be used to generate
sizeable libraries of potentially biologically active compounds.
R4
R3
R3
O
R2
R2
N
HN
TMSCl
R4
O
O
+
N
N
N
N
H
N
R1
3
N
H
R1
74-94%
4
5
HN
: R4 = Ph
4a
: R1 = R2 = Me, R3
5a
=
=
-Bu, R4 = Ph
R3
n
R2
O
R3
O
R2
O
N
HN
TMS-Cl
: R4 = 4-MeOC6H4
n
1 = R2 = Me, R3
-Bu, R4 = 4-ClC6H4
4b
4c
5b
:
R
+
O
O
N
N
: R4 = 4-ClC6H4
R1 = R2 = Me, R3 = Bn, R4 = Ph
:
N
H
N
5c
N
R1
N
N
R1
H
H
: R4 = 4-MeCO2C6H4
: R4 = 3-NO2C6H4
1 = R2 = Me, R3 = Bn, R4 = 4-ClC6H4
4d
5d
:
R
R1 = Ph, R2 = Me, R3 = Ph, R4 = Ph
5e
:
4e
4f
3a,b,e
6
7
82-87%
R4 = 4-CF3C6H4
R1 = Ph, R2 = Me, R3 = Ph, R4 = 4-MeOC6H4
5f
:
:
: R4 = 3-CF3C6H4
1 = Ph, R2 = Me, R3 = Ph, R4 = 4-ClC6H4
4g
5g
:
R
R1 = R2 = Me, R3
=
7a
:
n
-Bu
5h
:
R
1 = Ph, R2 = Me, R3 = Ph, R4 = 4-MeCO2C6H4
R1 = R2 = Me, R3 = Et
R1 = 4-ClC6H4, R2 = Me, R3
7b
:
R1 = Ph, R2 = Me, R3 = Ph, R4 = 3-NO2C6H4
R1 = Ph, R2 = Me, R3 = Ph, R4 = 4-CF3C6H4
R1 = Ph, R2 = Me, R3 = Ph, R4 = 3-CF3C6H4
n
5i
:
7c
:
n
-Bu
=
5j
:
Scheme 3. The preparation of isatin-derived pyrazolo[3,4-d]-
4,5-dihydropyrimidin-6-ones. Reagents and conditions: open-
chain urea 3, isatin (6), chlorotrimethylsilane, DMF, 100 °C.8
5k
:
R1 = 4-ClC6H4, R2 = Me, R3
=
-Bu, R4 = Ph
5l
:
5m
:
R
R
R
R
1 = 4-ClC6H4, R2 = Me, R3 = Et, R4 = Ph
References and notes
1 = 4-ClC6H4, R2 = Me, R3 = Et, R4 = 4-MeOC6H4
5n
:
1. Elnagdi, M. H.; Al-Awadi, N.; Abdelhamid, I. A. In
Comprehensive Heterocyclic Chemistry III, Katritzky, A. R.;
Ramsden, C. A.; Scriven, E. F. V.; Taylor, R. J. K. Elsevier,
Oxford, 2008. Vol. 10, p. 599.
1 = 4-ClC6H4, R2 = Me, R3 = Et, R4 = 4-ClC6H4
5o
:
1
= -Pr, R2 = H, R3
=
-Bu, R4 = Ph
n
5p
:
i
2. According to the DrugBank database (www.drugbank.ca) there is
presently 1 marketed drug and 14 experimental drug candidates
containing a substituted pyrazolo[3,4-d]pyrimidine unit.
3. Pacher, P.; Nivorozhkin, A.; Szabó, C. Pharm. Rev. 2006, 58,
87−114.
Scheme 2. The preparation of pyrazolo[3,4-d]-4,5-
dihydropyrimidin-6-ones. Reagents and conditions: open-
chain urea 3, aldehyde 4, chlorotrimethylsilane, DMF, 100
°C.8
4. Elnagdi, M. H.; Al-Awadi, N.; Erian, A. W. In Comprehensive
Heterocyclic Chemistry II, Katritzky, A. R.; Rees, C. W.; Scriven,
E. F. V. Eds.; Pergamon, Oxford, 1996, vol. 7, p. 431.
5. Ovcharova, I. M.; Zasosova, I. M.; Gerchikov, L. N.; Shuvalova,
M. E.; Golovchinskaya, E. S.; Liberman, S. S. Pharm. Chem. J.
1973, 7, 735−737.
As shown in Scheme 2, the cyclocondensation of ureas 3 with
aldehydes 4 in DMF, in the presence of TMSCl as the activator
of the C=O group and a water scavenger,9,10 gave pyrazolo[3,4-
d]-4,5-dihydropyrimidin-6-ones
5 in 74-94% yields. The
6. Das, J.; Moquin, R. V.; Pitt, S.; Zhang, R.; Shen, D. R.; McIntyre,
K. W.; Gillooly, K.; Doweyko, A. M.; Sack, J. S.; Zhang, H.;
Kiefer, S. E.; Kish, K.; McKinnon, M.; Barrish, J. C.; Dodd, J. H.;
Schieven, J. L.; Leftheris, K. Bioorg. Med. Chem. Lett. 2008, 18,
2652−2657.
structures and high purities of compounds 5 were confirmed by
1H and 13C NMR spectroscopy, LC-MS, and elemental analysis.
Thus, signals pertaining to a pyrazole C-4 proton in the 1H NMR
spectra of compounds 3 appearing at about 6.3-6.5 ppm were not
present in the corresponding spectra of compounds 5.
Additionally, only one amide N-H proton signal (pertaining to
position 7 of the pyrazolo[3,4-d]-4,5-dihydropyrimidin-6-one
7. Ryabukhin, S. V.; Granat, D. S.; Plaskon, A. S.; Shivanyuk, A. N.;
Tolmachev, A. A.; Volovenko, Y. M. ACS Comb. Sci. 2012, 14,
465−470.
8. In a typical procedure, DMF (1 mL), urea 3 (1 mmol), TMSCl (3
mmol) and the carbonyl compound (1.1 mmol), were placed in a
10 mL pressure tube. The tube was sealed and heated at 100 ºC for
8 h. The mixture was diluted with deionized H2O (8 mL) and
sonicated at room temperature for 2 h. The precipitated product
was filtered and washed with 5% aq. NaHCO3 (8 mL), and then
with i-PrOH (1 mL) and MeCN (1 mL). Analytically pure samples
were obtained through crystallization from MeCN.
1
scaffold) was found in the H NMR spectra of compounds 5.
Finally, the 1H NMR spectra of compounds
5 have a
characteristic proton signal at about 5.5 ppm that corresponds to
position 4 of the pyrazolo[3,4-d]-4,5-dihydropyrimidin-6-one
ring system. The 13C NMR spectra revealed that the pyrazole C-4
carbon signal appeared at ca. 88-92 ppm and 103-106 ppm in
compounds 3 and 5, respectively. The latter signal indicates a
quaternary carbon in the spectra of compounds 5. All these
9. For a review, see: Volochnyuk, D. M.; Ryabukhin, S. V.; Plaskon,
A. S.; Grygorenko, O. O. Synthesis 2009, 22, 3719−3743.

3
10. For recent similar transformations, see: (a) Ryabukhin, S. V.;
Plaskon, A. S.; Bondarenko, S. S., Ostapchuk, E. N.; Grygorenko,
O. O.; Shishkin, O. V.; Tolmachev, A. A. Tetrahedron Lett. 2010,
51, 4229–4232. (b) Ryabukhin, S. V.; Plaskon, A. S.; Boron, S.
Y.; Volochnyuk, D. M.; Tolmachev, A. A. Mol. Divers. 2011, 15,
189-195. (c) Ryabukhin, S. V.; Panov, D. M.; Plaskon, A. S.;
−635
Grygorenko, O. O. ACS Comb. Sci. 2012, 14, 631
. (d)
Ryabukhin, S. V.; Panov, D. M.; Plaskon, A. S.; Tolmachev, A.
A.; Smaliy, R. V. Monatsh. Chem. 2012, 143, 1507–1517. (d)
Ryabukhin, S. V.; Granat, D. S.; Plaskon, A. S.; Volochnyuk, D.
M.; Shivanyuk, A. Synlett 2013, 24, 2675−2678.
Supplementary Material
Supplementary data (experimental procedures and spectral
data) associated with this article can be found, in the online
version, at http://dx.doi.org/

4
Tetrahedron
•
First substituted pyrazolo[3,4-d]-4,5-
dihydropyrimidin-6-ones are reported.
•
•
•
•
The compounds are prepared by a new two-step
procedure from commercial chemicals.
Up to four different groups is introduced into the
title scaffold (19 examples).
Both, intermediates and the title species are easily
purified by crystallization.
The reported method is suitable for the parallel
synthesis of the title structures.