A one step synthesis of 1-alkylpyrazolo[5,4-d]pyrimidines

Article abstract of DOI:10.1016/j.tetlet.2008.10.065

A new synthesis of 1-alkylpyrazolo[5,4-d]pyrimidines is described. The reaction of 4,6-dichloropyrimidine-5-carbaldehyde with various substituted hydrazines provides such compounds in a single step from commercially available starting materials. This method has advantages over methods currently described in the literature for the construction of such ring systems.

Full text of DOI:10.1016/j.tetlet.2008.10.065

Tetrahedron Letters 49 (2008) 7395–7397
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Tetrahedron Letters
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A one step synthesis of 1-alkylpyrazolo[5,4-d]pyrimidines
Scott Boyd a, Leonie Campbell a, Wensheng Liao b, Qinghong Meng b,
Zuozhong Peng b, Xiaoping Wang b, Michael J. Waring a,
*
a AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom
b WuXi PharmaTech Co., Ltd, No. 1 Building, 288 FuTe ZhongLu, Shanghai, 200131, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 May 2008
Revised 3 October 2008
Accepted 14 October 2008
Available online 18 October 2008
A new synthesis of 1-alkylpyrazolo[5,4-d]pyrimidines is described. The reaction of 4,6-dichloropyrim-
idine-5-carbaldehyde with various substituted hydrazines provides such compounds in a single step from
commercially available starting materials. This method has advantages over methods currently described
in the literature for the construction of such ring systems.
Ó 2008 Elsevier Ltd. All rights reserved.
1-Alkylpyrazolo[5,4-d]pyrimidines 1 (Fig. 1) are an important
class of compounds for the pharmaceutical industry. Such sub-
structures are found in compounds spanning a range of biological
activity from kinase inhibitors such as 21 to ion channel blockers
such as 32 and receptor antagonists such as 4.3 As part of a cam-
paign to develop libraries based on this template, we had cause
to investigate the synthesis of chloro-substituted derivatives such
as 5 substituted with a range of different alkyl and aryl groups at
the 1-position with the 1-substituent originating from the appro-
priately substituted hydrazine.
of the hydrazine with a 2-alkoxy-1,1-dicyanoalkene4 or equiva-
lent5 to obtain the pyrazole derivative, onto which the fused
pyrimidine is annulated and chlorinated (Scheme 1). This sequence
requires multiple discrete steps, and the conditions involved are
incompatible with a number of functional groups, in particular
additional nitrile functionality. A more efficient method for achiev-
ing such a transformation would be to condense a substituted
hydrazine with 4,6-dichloropyrimidine-5-carbaldehyde allowing
formation of the desired ring system in a single step. Such a trans-
formation is known for chloroformylpyridines,6 and condensations
of hydrazine itself with such pyrimidinylaldehydes7 and pyrimidi-
nylketones have been reported,8,9 and related transformations
Perhaps the most common method for the preparation of such
systems reported in the literature is the stepwise condensation
NH2
OEt
N
OEt
N
N
N
N
H
N
O
Cl
F
N
HN
N
N
N
N
Cl
N
N
N
N
N
N
N
O
N
N
N
OEt
N
N
H
N
N
N
S
CF3
N
N
N
N
NH2
R
R
1
2
3
4
5
Figure 1.
* Corresponding author. Tel.: +44 1625 230942; fax: +44 1625 516667.
E-mail address: mike.j.waring@astrazeneca.com (M. J. Waring).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.065

7396
S. Boyd et al. / Tetrahedron Letters 49 (2008) 7395–7397
Cl
N
CN
CN
O
NC
RO
H
N
POCl3
N
HCO2H
HN
N
R
NH2
N
N
H2N
N
N
R
N
N
R
R
Cl
N
O
N
Cl
Scheme 1.
have been carried out on solid support to yield pyrimidone prod-
ucts.10 Such a transformation of 4,6-dichloro-2-phenylpyrimi-
dine-5-carbaldehyde and phenylhydrazine proceeding with
concomitant displacement of a second hydrazine molecule to form
N -[(1,6-diphenyl-7H-pyrazolo[4,5-e]pyrimidin-4-ylidene)amino]-
aniline has been reported.11
Cl
N
Cl
N
N
RNHNH2
Et3N
N
O
N
N
Cl
R
6
Hydrazine
Hence, the condensation of 4,6-dichloropyrimidine-5-carbalde-
hyde 6 with phenylhydrazine in the presence or absence of trieth-
ylamine as a base was investigated. After a short reaction screening
process, it was shown that such a transformation to form 4-chloro-
Entry
1
Product
Isolated Yield
54%
Cl
N
N
F
N
N
NH2
1-phenyl-1H-pyrazolo[3,4-d]pyrimidine
7
is indeed possible
N
H
(Scheme 2),12 and proceeds more efficiently in the presence of base
and in ethereal rather than alcoholic solvents. The regioisomer 8
has also been isolated from the reaction (2:1 ratio) but is readily
separable by chromatography. Its identity was established by the
observance of an NOE between the phenyl o-hydrogen and hydro-
gen of the pyrazole ring of 8 which is absent in 7. In addition, the
product 4-chloro-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine has
been observed to react readily with methanol on dissolution to
form the corresponding methyl ether (data not shown) and has
been found to be sensitive to adventitious moisture. These factors
could contribute to the discrepancy between the measured LC–MS
conversion and the isolated yield although the corresponding 1-
phenyl-5H-pyrazolo[4,5-e]pyrimidin-4-one hydrolysis product
has not been isolated during chromatography.
Subsequently, it emerged that this reaction can be applied to a
range of more diverse hydrazines (Scheme 3). The reaction is appli-
cable to electron-rich aryl- (entry 2) and electron poor heteroaryl
(entries 3 and 4) hydrazines as well as a range of alkyl hydrazines
(entries 5 to 8) including those with a sterically encumbered nitro-
gen (entry 8). Additionally, the reaction is compatible with an addi-
tional nucleophilic (hydroxyl) functionality (entry 7) albeit with
diminished yield. Gratifyingly, the undesired regioisomer akin to
8 was not observed in any of these subsequent transformations.
It has been observed that when carrying out this reaction on
unpurified commercial 4,6-dichloropyrimidine-5-carbaldehyde,
F
Cl
N
N
N
MeO
N
2
3
4
NH2
69%
53%
72%
N
H
OMe
Cl
N
N
N
N
N
N
NH2
N
H
N
Cl
N
N
N
N
N
NH2
N
H
Cl
N
N
N
NH2
N
H
N
5
49%
Cl
N
N
MeNHNH2
HO
6
7
N
36%
31%
NOE 10%
Cl
N
N
N
N
Cl
Cl
N
H
H
N
Cl
N
NHNH2
N
N
N
O
N
N
NH2
+
+
N
N
N
N
H
Cl
7
8
6
OH
Cl
N
Isolated
yield of 7
Conditions
LCMS
conversion
N
N
NH2
EtOH, Et3N, 65 ºC, 40 min
THF, 65 ºC, 40 min
THF, Et3N, 65 ºC, 40 min
30%
40%
80%
-
-
8
51%
N
H
N
54%12
Scheme 2.
Scheme 3.

S. Boyd et al. / Tetrahedron Letters 49 (2008) 7395–7397
7397
NOE 10.5%
Cl
N
NH2
HN
Cl
CF3
N
N
CF3
Cl
N
H
Cl
N
N
H
N
N
N
N
N
O
CF3
N
N
Cl
Cl
Cl
6
9
Cl
Scheme 4.
solvent was removed under vacuum and the crude product was purified by
flash chromatography on silica to give the product (3.5 g, 54%).
the reaction appears to be sensitive to changes in conditions and,
on occasions, failed to proceed to the desired products. The reac-
tion proceeds much more reliably with freshly prepared sub-
strate.13 In cases where the hydrazine is very electron poor such
as (5-chloro-3-methylpyridin-2-yl)hydrazine, (3-methylpyrazin-
2-yl)hydrazine and (5-chloropyrimidin-4-yl)hydrazine, the reac-
tion under the above conditions has been observed to halt at the
uncyclised species such as 9 (Scheme 4) which is potentially an
intermediate en route to the final products. In these cases pro-
longed heating at higher temperatures can effect the final cyclisa-
tion, although, in our hands, we have found this reaction to be
capricious. Moreover, it is suggested by NOE studies that 9 exists
predominantly in the trans-configuration and presumably this
would further disfavour the subsequent cyclisation step.
Nevertheless, in the majority of cases, this methodology allows
access in a single step to a diverse range of 1-alkyl-4-chloropyraz-
olo[3,4-d]pyrimidines. Such chloro derivatives are known to un-
dergo a wide range of transformations including nucleophilic
displacements5,14 and palladium couplings,15 and can also be
reduced to the corresponding CH derivatives.16 Hence, this work
represents a new, general method for preparation of the 1-alkyl-
pyrazolo[4,5-d]pyrimidine system which has advantages over
existing methods.
4-Chloro-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine: 1H NMR (400 MHz, CDCl3): d
7.44 (t, J = 6.8 Hz, 1H), 7.60 (t, J = 6.8 Hz, 2H), 8.22 (d, J = 8.0 Hz, 2H), 8.38 (s,
1H), 8.91 (s, 1H). 13C NMR (100 MHz, CDCl3): 115.38, 121.82, 127.69, 129.59,
133.52, 138.46, 153.10, 155.35, 155.41. IR (KBr) 3110 cmÀ1. HRMS: m/z calcd
for C11H8N4Cl (M+H+): 231.0432; found: 231.0434.
4-Chloro-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine: 1H NMR (300 MHz,
CDCl3) d 7.26 (t, J = 8.1 Hz, 2H), 8.17 (d, J = 8.1 Hz, 2H), 8.34 (s, 1H), 8.88 (s, 1H);
13C NMR (100 MHz, CDCl3) d 115.30, 116.36, 116.59, 123.53, 123.61, 133.55,
134.61, 152.98, 155.44, 155.51, 161.73; IR (KBr) 3061, 3086, 3108 cmÀ1
;
HRMS: m/z calcd for C11H7N4ClF (M+H+): 249.0338; found: 249.0343.
4-Chloro-1-(4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine: 1H NMR (300 MHz,
CDCl3) d 3.88 (s, 3H), 7.07 (d, J = 9.0 Hz, 2H), 8.14 (d, J = 9.0 Hz, 2H), 8.32 (s, 1H),
8.85 (s, 1H); 13C NMR (100 MHz, CDCl3) d 55.61, 114.52, 114.82, 123.36,
131.36, 132.86, 152.51, 155.03, 155.12, 158.89; IR (KBr) 2973, 2940, 2841
cmÀ1; HRMS: m/z calcd for C12H10ON4Cl (M+H+): 261.0538; found: 261.0532.
4-Chloro-1-pyridin-2-yl-1H-pyrazolo[3,4-d]pyrimidine: 1H NMR (300 MHz, CDCl3)
d 7.38 (t, J = 6.9 Hz, 1H), 7.93 (t, J = 8.4 Hz, 1H), 8.25 (d, J = 8.4 Hz, 1H), 8.50 (d,
J = 4.8 Hz, 1H), 8.84 (s, 1H), 9.31 (s, 1H); 13C NMR (100 MHz, CDCl3) d 114.29,
115.48, 122.40, 125.05, 139.93, 148.99, 150.87, 155.58, 156.21, 158.52; IR (KBr)
3149 cmÀ1
232.0378.
;
HRMS: m/z calcd for C10H7N5Cl (M+H+): 232.0384; found:
2-(4-Chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-quinoline: 1H NMR (300 MHz, CDCl3)
d 7.58 (t, J = 7.8 Hz, 1H), 7.77 (t, J = 7.8 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H) 8.06 (d,
J = 8.4 Hz, 1H), 8.38 (d, J = 8.7 Hz, 1H), 8.47 (d, J = 9.0 Hz, 1H), 8.86 (s, 1H), 9.51
(s, 1H); 13C NMR (100 MHz, CDCl3) d 109.87, 112.98, 126.06, 127.47, 127.90,
128.59, 128.66, 131.52, 140.86, 146.13, 149.02, 149.39, 158.95, 160.29; IR (KBr)
3088, 3111 cmÀ1; HRMS: m/z calcd for C14H9N5Cl (M+H+): 282.0541; found:
282.0544.
1-Benzyl-4-chloro-1H-pyrazolo[3,4-d]pyrimidine: 1H NMR (400 MHz, CDCl3) d
5.71 (s, 2H), 7.39 (m, 5H), 8.20 (s, 1H), 8.83 (s, 1H); 13C NMR (100 MHz, CDCl3):
51.51, 113.76, 128.16, 128.29, 128.81, 132.38, 135.54, 153.10, 154.70, 154.85;
IR (KBr) 2850, 2920, 2978, 3007, 3030, 3063, 3099 cmÀ1; HRMS: m/z calcd for
C12H10N4Cl (M+H+): 245.0594; found: 245.0589.
References and notes
1. Bilodeau, M. T.; Duggan, M. E.; Hartnett, J. C.; Lindsley, C. W.; Wu, Z.; Zhao, Z.
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Arzneim. Forsch. 1990, 40, 1328–1331; Burch, H. A. J. Med. Chem. 1968, 11, 79–
83.
4-Chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine: 1H NMR (400 MHz, CDCl3) d
4.18 (s, 3H), 8.18 (s, 1H), 8.80 (s, 1H); 13C NMR (100 MHz, CDCl3) d 29.67,
113.61, 131.88, 153.19, 154.52, 154.80; IR (KBr) 2861, 2922, 3102, 3166 cmÀ1
;
HRMS: m/z calcd for C6H6N4Cl (M+H+): 169.0276; found: 169.0276.
2-(4-Chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-ethanol: 1H NMR (400 MHz, CDCl3) d
4.17 (t, J = 5.2 Hz, 2H), 4.69 (t, J = 5.2 Hz, 2H), 8.21 (s, 1H), 8.80 (s, 1H); 13C NMR
(100 MHz, CDCl3) d 50.76, 61.20, 113.82, 132.36, 153.34, 154.58, 155.18; IR
(KBr) 3298, 3097, 2963, 2923, 2880, 2851 cmÀ1
C7H8ON4Cl (M+H+): 199.0381; found: 199.0383.
; HRMS: m/z calcd for
1-tert-Butyl-4-chloro-1H-pyrazolo[3,4-d]pyrimidine: 1H NMR (400 MHz, CDCl3)
d 1.86 (s, 9H), 8.12 (s, 1H), 8.77 (s, 1H). 13C NMR (100 MHz, CDCl3) d 29.41,
61.72, 115.02, 130.49, 153.00, 153.32, 154.78; IR (KBr) 2875, 2935, 2983, 3046,
5. Hayashi, E.; Higashino, T.; Suzuki, S.; Kato, T.; Kohno, M.; Shinoda, H.; Mizuno,
D. Yakugaku Zasshi 1977, 97, 1328–1333.
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;
3108 cmÀ1 HRMS: m/z calcd for C9H12N4Cl (M+H+): 211.0745; found:
211.0743.
13. Prepared according to: Klötzer, W.; Herberz, M. Monatsh. Chem. 1965, 96,
1567–1572. Material prepared in this way is a colourless crystalline solid.
Commercial material has been observed to be coloured. The commercial
material can be purified by flash chromatography prior to reaction to give
similar results to freshly prepared substrate.
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12. Representative experimental procedure: A suspension of 4,6-dichloropyrimidine-
5-carbaldehyde (5 g, 28.4 mmol) and phenylhydrazine (31.2 mmol) in
anhydrous THF (150 mL) and triethylamine (3.9 mL, 28.4 mmol) was stirred
for 10 min at room temperature and then heated to 65 °C for 50 min. The
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4803–4812.