Efficient and regioselective N-1 alkylation of 4-chloropyrazolo[3,4-d]pyrimidine

Article abstract of DOI:10.1016/j.tetlet.2007.02.116

Efficient and N-1 selective alkylation of 4-chloropyrazolo[3,4-d]pyrimidine can be achieved when the heterocycle is reacted with alcohols under Mitsunobu conditions. The 1-alkyl-pyrazolo[3,4-d]pyrimidines formed can be functionalized further according to known methods, to give a variety of 1,4-disubstituted pyrazolo[3,4-d]pyrimidines. The first example of a palladium-catalyzed coupling reaction on a 4-halopyrazolo[3,4-d]pyrimidine is described.

Full text of DOI:10.1016/j.tetlet.2007.02.116

Tetrahedron Letters 48 (2007) 3057–3059
Efficient and regioselective N-1 alkylation
of 4-chloropyrazolo[3,4-d]pyrimidine
Morten Brændvang and Lise-Lotte Gundersen*
Department of Chemistry, University of Oslo, PO Box 1033, Blindern, N-0315 Oslo, Norway
Received 28 January 2007; revised 13 February 2007; accepted 23 February 2007
Available online 1 March 2007
Abstract—Efficient and N-1 selective alkylation of 4-chloropyrazolo[3,4-d]pyrimidine can be achieved when the heterocycle is
reacted with alcohols under Mitsunobu conditions. The 1-alkyl-pyrazolo[3,4-d]pyrimidines formed can be functionalized further
according to known methods, to give a variety of 1,4-disubstituted pyrazolo[3,4-d]pyrimidines. The first example of a palladium-
catalyzed coupling reaction on a 4-halopyrazolo[3,4-d]pyrimidine is described.
Ó 2007 Elsevier Ltd. All rights reserved.
1,4-Disubstituted pyrazolo[3,4-d]pyrimidines have at-
tracted attention as potential drugs or molecular tools.
Some recently reported applications for this class of
compounds are, for example, inhibition of various
kinases,1 inhibition of phosphodiesterase 9,2 as well as
inhibition of viral and bacterial growth.3 In most cases
pyrazolo[3,4-d]pyrimidines are formed in several steps
from a suitable pyrazole, or less frequently from a
pyrimidine.4 However, allopurinol (1) (Scheme 1) is a
commercially available pyrazolo[3,4-d]pyrimidine and
thus an attractive starting point for the synthesis of
1,4-difunctionalized pyrazolo[3,4-d]pyrimidines. Allopu-
rinol can readily be transformed into the corresponding
4-chloro derivative 2,5 and chlorine in the pyrazolo-
[3,4-d]pyrimidine 4-position is readily displaced by S-,
N- and O-nucleophiles or anions of active methylene
reagents.4a Carbon–carbon bond formation at the
4-position has also been achieved by metal-halogen
exchange on 4-halopyrazolo[3,4-d]pyrimidines and sub-
sequent trapping of the organometallic species with a
carbonyl compound.6 The major challenge identified in
transformation of allopurinol (1) into a 1,4-difunction-
alized pyrazolo[3,4-d]pyrimidine was selective and
efficient introduction of the N-1 substituent. This
heterocyclic ring system is surprisingly unreactive under
standard alkylation reactions employing an alkyl halide
and a base. 1-Alkylated products have been obtained in
reasonable yields when 4-halopyrazolo[3,4-d]pyrimidine
(2) was reacted with an alkyl iodide in the presence of
cesium carbonate,7 but substantial amounts of the N-2
alkylated isomer were also formed and alkyl iodides
are normally not as easily accessible as the correspond-
ing chlorides or bromides. Structurally related hetero-
cycles like purines8 and 3-deazapurines9 are often
efficiently N-alkylated by the Mitsunobu reaction, an
attractive methodology since alcohols instead of alkyl
halides are used as alkylating agents. Hence we decided
to study N-alkylation of 4-chloropyrazolo[3,4-d]pyrimi-
dine (2) under Mitsunobu conditions.
Chloropyrazolo[3,4-d]pyrimidine 2 was reacted with
alcohols in the presence of triphenylphosphine and
DIAD (Scheme 1, Table 1).10
When compound 2 was alkylated with n-butanol under
Mitsunobu conditions, 1-butyl-4-chloropyrazolo[3,4-d]-
pyrimidine 3a was isolated as the only product in
77% yield. However, formation of other products in
minor amounts, co-eluting with the reduced form of
DIAD or triphenylphosphine oxide formed during the
reaction, cannot be excluded. The presence of these
co-products also precluded a thorough study of prod-
ucts formed by NMR spectroscopy of the crude prod-
uct. In reactions with several other alcohols, minor
amounts of the N-2 alkylated isomer 4 were isolated,
but the selectivity towards N-1 alkylation was generally
high. The Mitsunobu protocol compared favourably
with the previously published N-alkylation employing
alkyl iodide and cesium carbonate,7 which gave a mix-
ture of N-1 and N-2 alkylated products and a low yield
*
Corresponding author. Tel.: +47 228 57019; fax: +47 228 55507;
e-mail: l.l.gundersen@kjemi.uio.no
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.02.116

3058
M. Brændvang, L.-L. Gundersen / Tetrahedron Letters 48 (2007) 3057–3059
Scheme 1. Reagents and conditions: (a) ROH, PPh3, DIAD, THF; (b) RI, Cs2CO3, DMF.
Table 1. N-Alkylation of 4-chloropyrazolo[3,4-d]pyrimidine (2)
R
Methoda
Temperature (°C)
Time (h)
Yield (%) 3
Yield (%) 4
Yield (%) 5
b
b
n-Bu
n-Bu
n-Hex
CH3OCH2CH2
i-Bu
c-Hex–CH2
(2-Tetrahydrofuryl)CH2
p-CH3O–C6H4–CH2
p-CH3O–C6H4–CH2
CH2@CHCH2
HC„CCH2
HC„CCH2CH2
i-Pr
a
b
a
a
a
a
a
a
b
a
a
a
a
a
a
0–rt
0
0
0
0–rt
0
0
0–rt
0
0
0
6
2
3
2.5
6
2.5
3
6
3
3
77, 3a
26, 3a
72, 3b
59, 3c
72, 3d
65, 3e
39, 3f
47, 3g
32, 3g
62, 3h
48, 3i
64, 3j
60, 3k
73, 3l
21, 3m
—
—
11, 4a
b
—
—
—
—
—
—
—
4, 5b
b
b
—
b
b
—
b
10, 5e
b
b
—
c
c
—
<8, 4gd
17, 4h
—
7, 5h
8, 5i
b
0.75
0.75
3.5
1
—
0
0
0
D
6, 4j
b
15, 5j
13, 5k
11, 5l
—
c-Pent
c-Hex
3, 4l
b
b
6
—
—
a See Scheme 1.
b Not isolated.
c A ca. 3:1 mixture of 4g and 5g was isolated indicating the formation of ca 20% of 4g.
d Not isolated pure.
of the desired isomer 3a. The identification of isomers 3
and 4 was mainly based on 13C NMR spectroscopy as
described previously.7
As mentioned above, 4-chloropyrazolo[3,4-d]pyrimi-
dines are prone to nucleophilic displacement of the
halogen,4a and several nucleophilic species are present
in the reaction mixture during the Mitsunobu reaction.
In some cases we isolated minor amounts of com-
pounds 5 containing a DIAD derived substituent at
C-4, but we never isolated any 4-alkoxypyrazolo[3,4-d]-
pyrimidines which theoretically could have been formed
from nucleophilic attack of the alcohols used. Once
As can be seen from Table 1, a variety of alcohols,
including allylic, propargylic and benzylic alcohols,
reacted readily with the chloropyrazolo[3,4-d]pyrimidine
2 to give 1-substituted compounds 3, generally with high
regioselectivity and in good yields compared to existing
methodology. The lowest regioselectivity was obtained
in the introduction of the p-methoxybenzyl group, but
compound 3g was still isolated in better yield from the
Mitsunobu reaction than by alkylation with p-meth-
oxybenzyl iodide, a commercially unavailable iodide.11
Also, secondary alkyls could be introduced, but the
reaction with cyclohexanol required reflux temperature
and the yield of product 3m was rather modest. The,
inferior performance of cyclohexanol in Mitsunobu
reactions has been reported before.12
formed, 9-alkyl-4-chloropyrazolo[3,4-d]pyrimidines
3
may easily be derivatized further by nucleophilic
substitutions to give a variety of 1,4-disubstituted
pyrazolo[3,4-d]pyrimidines as discussed above. We
chose, to the best of our knowledge for the first time,
to subject a 4-chloropyrazolo[3,4-d]pyrimidine to a
palladium catalyzed coupling reaction. Stille coupling
between compound 3g and (2-furyl)tributyltin gave
the furyl derivative 6 in high yield (Scheme 2).
Compound 6 is an isomer of the previously reported
Scheme 2. Reagents and conditions: (a) (2-furyl)tributyltin, (Ph3P)2PdCl2, DMF, 90 °C.

M. Brændvang, L.-L. Gundersen / Tetrahedron Letters 48 (2007) 3057–3059
3059
antimycobacterial purine 7.13 Biological activity of 6
will be published elsewhere.
(k) Smalley, T. L., Jr.; Peat, A. J.; Boucheron, J. A.;
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Acknowledgement
The Norwegian Research Council is gratefully acknowl-
edged for partial financing of the Bruker Avance instru-
ments used in this study.
3. (a) Chern, J.-H.; Shia, K.-S.; Hsu, T.-A.; Tai, C.-L.; Lee,
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Supplementary data
Spectroscopic data for all new compounds and a proce-
dure for the synthesis of compound 6, can be found in
the supplementary data. Supplementary data associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2007.02.116.
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10. General procedure for N-alkylation of compound 2 under
Mitsunobu conditions: Triphenylphosphine (393 mg,
1.50 mmol) and 4-chloro-1H-pyrazolo[3,4-d]pyrimidine
(2) (154 mg, 1.00 mmol) were dissolved in dry THF
(5 mL) under N2 and cooled to 0 °C for 15 min. The
alcohol (1.00 mmol) was added immediately followed by
dropwise addition of DIAD (300 lL, 1.50 mmol) over
2 min. After stirring at the temperature and time given in
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