N. Todorovic et al. / Tetrahedron Letters 52 (2011) 5761–5763
5763
H
N
NH2
OEt
NC
H2N
HCONH2
N
CN
N
N
MW 100oC
30 min
MW 180oC
30 min
N
N
H2N
N
9
CN
7
8
NH2
NH2
Br
N
NH2
N
R1
N
R1
N
R2-B(OH)2
Br2
HCO2H
HCl
N
N
Pd2dba3, PA-Ph
MW 55oC, 30 min.
N
N
N
N
N
N
H
10
11
12
Scheme 2. Synthetic route to 3-aryl-1H-pyrazolo[3,4-d]pyrimidin-4-amines (12).
Although 4 is commercially available, a more cost-effective
route involves the treatment of 5-amino-1H-pyrazole-4-
carbonitrile (2) with formamide (3). Microwave irradiation at
200 °C for 30 min allowed for the preparation of (4) in excellent
yields. Furthermore, simple filtration allowed for the isolation of
the pyrazolopyrimidine.
Iodination of 4 was achieved by treatment with N-iodosuccini-
mide in DMF using microwave irradiation at 90 °C for 10 min. The
3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (5) produced is an
ideal scaffold for our studies.
Table 2
Yields of 1-t-butyl-3-aryl-1H-pyrazolo[3,4-d]pyrimidin-4-amines (11) and 3-aryl-1H-
pyrazolo[3,4-d]pyrimidin-4-amines (12)
Entry
R1
Yielda (1) %
Yielda (12) %
Cl
1
85
92
CH3
2
81
99
Alkylation at N1 was then carried out using Mitsunobu chemis-
try wherein 5 is treated with an alcohol in the presence of PPh3 and
DIAD. While yields of 6 (Table 1, entries 1, 5, 17, and 18) ranged
from moderate to excellent, the need for repeated chromatography
to remove the concomitant triphenylphosphine oxide resulted in
the development of an alternate alkylation method. Treatment of
5 with K2CO3 and bromobutane (to give Table 1, entry 4) or iso-
butylbromide (to give Table 1, entry 16) resulted in good yields
of N1 alkylation product 6. It should be noted that these two ap-
proaches were only suitable for the introduction of primary alkyl
groups at N1. Access to tertiary substitutents required the utiliza-
tion of a de novo synthetic route (Scheme 2).
a
Isolated yields.
deprotected using formic acid and HCl to give the desired systems
12 (see Table 2).
Overall, application of the microwave-assisted protocols
described above represent a useful means to access libraries of
N1- and C3-substituted pyrazolo[3,4-d]pyrimidine in a rapid and
efficient manner.
Acknowledgments
Finally, arylation at C3 was achieved via Suzuki cross-coupling
taking advantage of a Pd-catalytic system containing the 1,3,5,7-
tetramethyl-2,4,8-trioxa-6-phenyl-6-phosphaadamantane (PA-Ph)
ligand developed in our laboratory.6 Microwave irradiation of 6
with a variety of boronic acids in the presence of Pd2dba3 and
the PA-Ph ligand allowed for the production of the desired N1-
and C3-substituted pyrazolo[3,4-d]pyrimidines (1).
The authors thank the M. G. DeGroote Institute for Infectious
Disease Research (McMaster University), the Natural Sciences
and Engineering Research Council of Canada, the Canadian Founda-
tion for Innovation and the Ontario Innovation Trust for their
financial support.
Access to the monosubstituted pyrazolopyrimidines proved to
be more complicated than initially anticipated. For example,
attempts to synthesize 1 where R2 = H by using the Mitsunobu or
alkylation chemistry developed above on 1H-pyrazolo[3,4-d]pyr-
imidin-4-amine (4) gave multiple products in poor yields. This
could be overcome via the use of a Pd-catalyzed dehalo-hydroge-
nation reaction. Compounds of the general type 6 could be
de-iodinated quantitatively by treatment with Pd2dba3, PA-Ph
and Cs2CO3 in cyclohexane with microwave irradiation at 120 °C
for 30 min (e.g., to give entries 19 and 20 in Table 1).
The synthesis of compounds of the general type 12 (Scheme 2)
via a Suzuki reaction using 5 as a coupling partner also proved to
be low yielding. In order to access these systems, we determined
that 3-bromo-1-tert-butyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine
(10) would be an ideal scaffold as arylation at C3 could be followed
by a deprotection of the t-butyl moiety to give the desired 12.
The de novo production of requisite scaffold (presented in
Scheme 2) involved the condensation of ethoxymethylene malon-
onitrile (7) with t-butylhydrazine to give 8 followed by treatment
with formamide to give 9 and bromination to give 10. Suzuki reac-
tions on this substrate smoothly provided systems such as 11
(using the procedures developed above) that could readily be
Supplementary data
Supplementary data (sample experimental procedures and
spectral data) associated with this article can be found, in the on-
References and notes
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