Iodobenzene diacetate-promoted N-N and N-O bond formation for pyrazolo- and isoxazolopyrimidine syntheses

Article abstract of DOI:10.3987/COM-08-S(D)34

Pyrazolo[3,4-d]pyrimidine-4,6-dione derivatives were efficiently synthesized via the intramolecular N-N bond coupling of 5-iminomethyl-6-aminouracil derivatives using iodobenzene diacetate. The oxidative coupling was also applied to the analogous N-O bond

Full text of DOI:10.3987/COM-08-S(D)34

HETEROCYCLES, Vol. 79, 2009
669
HETEROCYCLES, Vol. 79, 2009, pp. 669 - 680. © The Japan Institute of Heterocyclic Chemistry
Received, 26th September, 2008, Accepted, 20th November, 2008, Published online, 21st November, 2008.
DOI: 10.3987/COM-08-S(D)34
IODOBENZENE DIACETATE–PROMOTED N–N AND N–O BOND
FORMATION FOR PYRAZOLO- AND ISOXAZOLOPYRIMIDINE
SYNTHESES
Yasunari Monguchi, Kazuyuki Hattori, Tomohiro Maegawa, Kosaku
Hirota,¶ and Hironao Sajiki*
Laboratory of Medicinal Chemistry, Gifu Pharmaceutical University, 5-6-1,
Mitahora-higashi, Gifu 502-8585, Japan. E-mail address: sajiki@gifu-pu.ac.jp
Abstract – Pyrazolo[3,4-d]pyrimidine-4,6-dione derivatives were efficiently
synthesized
via
the
intramolecular
N–N
bond
coupling
of
5-iminomethyl-6-aminouracil derivatives using iodobenzene diacetate. The
oxidative coupling was also applied to the analogous N–O bond formation
producing isoxazolo[3,4-d]primidine-4,6-dione derivatives.
This paper is dedicated to the memory of Dr. John Daly.
INTRODUCTION
Since allopurinol, pyrazolo[3,4-d]pyrimidin-4-one, was developed as a clinical medicine for the treatment
of hyperuricemia and gouty arthritic diseases based on the inhibition of xanthine oxidase,1 much attention
has been focused on the biological evaluation of the pyrazolo[3,4-d]pyrimidine derivatives.2,3 Recent
biological studies of such pyrazolopyrimidine derivatives have targeted a wide range of biomolecules,
such as Src protein kinases,4,5 EGF receptor tyrosine kinases,6 Abelson kinase,7 p38 MAP kinase,8 cyclic
cyclooxygenase-2,9 bacterial DNA polymerase III,10 mycobacterial lumazine synthase,11 adenosine A1
receptor,12 cannabinoid receptor type 1,13 etc. The synthetic methods for the construction of the
pyrazolo[3,4-d]pyrimidine ring system have involved the cyclization of the pyrazole5,7,8,12,14,15 or
pyrimidine intermediates,11,16 but the nitrogen–nitrogen (N–N) bond forming reaction was never used for
the cyclization of a pyrazole ring until our published communication related to the iodobenzene
diacetate-promoted N–N bond formation.17 Although the isoxazolo[3,4-d]pyrimidine derivatives were
structurally very similar to the pyrazolo[3,4-d]pyrimidine derivatives, they have been basically
synthesized by the isoxazole ring formation starting from the 5,6-disubstituted pyrimidine derivatives,18,19
and the ring closure reaction via the nitrogen–oxygen (N–O) bond formation appeared during the
thermolysis of the 5-acyl-6-azidouracils20,21 and photolysis of the 5-acyl-6-sulfiliminouracils.22
Hypervalent iodine reagents,23 such as iodobenzene diacetate and phenyliodine bis(trifluoroacetate), have

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HETEROCYCLES, Vol. 79, 2009
been used for the oxidative N–N17,24,25 and N–O26 bond formations to build the pyrazolo- and
isoxazoloarene motifs in past decade. We now describe the details of the iodobenzene diacetate-promoted
cyclization
method
for
the
preparation
of
pyrazolo[3,4-d]pyrimidine-4,6-diones
and
isoxazolo[3,4-d]pyrimidine-4,6-diones via the N–N and N–O bond creation, respectively.
RESULTS AND DISCUSSION
During the course of our study on the fused pyrimidine synthesis, we found that
5-[(dimethylamino)methylene]dihydro-6-imino-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione hydrochloride
(1), which was readily prepared by the reaction of the commercially available 6-amino-1,3-dimethyluracil
with phosphoryl chloride in dimethylformamide (DMF), underwent a nucleophilic attack on the
dimethylaminomethylene carbon at the 5-position of the pyrimidine ring by a nitrogen atom from a series
of amides, and subsequent cyclization afforded the pyrimido[4,5-d]pyrimidine derivatives (Scheme
1).27,28
O
O
O
Me
Me
Me
O
CH N
Me
O
CH NCOR
NH2
Me
O
RCONH2
N
N
N
N
N
NH•HCl
N
N
N
R
Me
Me
Me
1
Scheme 1. Pyrimido[4,5-d]pyrimidine synthesis
When we used excess amounts of primary amines in place of the amides as nucleophiles, the
6-amino-5-(substituted iminomethyl)-1,3-dimethyluracil derivatives (2)29 was stably obtained, which
were used as starting materials for the intramolecular N–N bond formation (Table 1). The addition of a
base, such as triethylamine (Et3N) or lithium hydride (LiH), increased the reaction efficiency due to the
enhanced nucleophilicity of the amine nitrogen atoms (Entries 1, 10–12); e.g., the use of n-butylamine
could be reduced to 1.1 equiv by the addition of 1.1 equiv of Et3N, while the reaction with 2.1 equiv of
n-butylamine gave 2j in only 31% yield (Entry 10).
Our attempts of the intramolecular N–N bond formation were initiated by the investigation of some
oxidants using 2a as a substrate. While the use of 4 equiv of N-bromosuccinimide resulted in the
formation of a complex mixture containing unreacted 2a, the oxidation with 4 equiv of lead tetraacetate in
DMF at rt gave the desired 5,7-dimethyl-2-phenylpyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (3a) in
47% yield. Furthermore, the employment of iodobenzene diacetate significantly improved the yield up to
87% (Entry 1). Therefore, we chose iodobenezene diacetate as the oxidant for the present cyclization. As
shown in Entries 1–7, the 5-aryl substituted iminomethyluracil derivatives (R = aryl: 2a–2g) were

HETEROCYCLES, Vol. 79, 2009
671
smoothly oxidized to afford the desired pyrazolo[3,4-d]pyrimidine derivatives (3a–3g) in good to
excellent yields. Although the 5-alkyl substituted iminomethyluracil derivatives (R = alkyl: 2h–2m) were
less reactive under the same reaction conditions, the addition of 2 equiv of LiH improved the N–N bond
formation efficiency (Entries 9–13). For example, the yield of the t-butyl substituted
pyrazolo[3,4-d]pyrimidine 3i was improved from 35% to 56% (Entry 9).
Table 1. Synthesis of 2-substituted 5,7-dimethylpyrazolo[3,4-d]pyrimidine-4,6-diones
O
O
O
Me
Me
Me
O
CH N
Me
O
CH NR
NH2
Me
O
RNH2 (2.1 equiv)
DMF, rt
PhI(OAc)2 (4.0 equiv)
DMF, 80 °C
N
N
N
N R
N
N
NH•HCl
N
N
Me
Me
Me
1
2
3
Entry
1
R
Ph
Precursor
2a
Yield (%)
78a
Time (h)
1
Product
3a
Yield (%)
87 (47)d
F
2
3
2b
2c
74
36
1
1
3b
3c
92
76
Cl
Cl
4
2d
43
2
3d
80
NO2
5
6
2e
2f
76
54
3
5
3e
3f
55
40
OMe
7
2g
86
5
3g
97
8
9
10
11
12
Me
t-Bu
n-Bu
c-Pent
c-Hex
2h
2i
2j
2k
2l
89
3
4
2
2
1
3h
3i
3j
3k
3l
61
60
35, 56e
85e
31, 83a
99b
72e
91c
68e,f
13
2m
63
1
3m
67e
CH2
a 1.1 equiv of primary amine and 1.1 equiv of Et3N were used. b 1.1 equiv of c-pentylamine and 1.1 equiv
c
d
of LiH were used. 1.2 equiv of c-hexylamine hydrochloride and 2.2 equiv of Et3N were used. Lead
tetraacetate (4.0 equiv) was used as an oxidant instead of PhI(OAc)4. e 2.0 equiv of LiH were added. f 2.5
equiv of iodobenzene diacetate were used.

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HETEROCYCLES, Vol. 79, 2009
We next explored the intramolecular N–O bond forming reaction using the 5-acyl-substituted
6-amino-1,3-dimethyl-2,4-pyrimidinedione derivatives (4a–4c) by iodobenzene diacetate (Table 2). The
oxidative cyclization in the presence of 2 equiv of LiH was successfully achieved to give the
corresponding 3-substituted 5,7-dimethylisoxazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione derivatives
(5a–5c) in good to excellent yields.
Table 2. Synthesis of isoxazolo[3,4-d]pyrimidine-4,6(5H,7H)-diones by the N–O bond formation
O
O
R
PhI(OAc)2 (2.5 equiv)
LiH (2.0 equiv)
Me
O
COR
NH2
Me
O
N
N
O
N
DMF, 80 °C
N
N
Me
Me
4a–4c
5a–5c
Entry
Substrate
R
Me
Et
Time (h)
4
3
0.5
Product
5a
5b
Yield (%)
1
2
3
4a
4b
4c
82
72
94
n-Pr
5c
A plausible mechanism for the intramolecular N–N bond formation is depicted in Scheme 2. The
oxidation would be initiated by the reaction of the iodobenzene diacetate with the amine nitrogen of 2
or/and its tautomer, 6-aminomethylidene-6-iminouracil (6). Iodobenzene would be dissociated from the
resulting intermediates A and B to give the corresponding nitrenium acetate ion pairs C and D,
respectively. Nitrenium ions are highly electrophilic and stabilized by the neighboring electron-donating
group such as aryl, alkoxy, and amino groups.25,30 In this study, the 5-arylimino-substituted uracils were
rather reactive compared with the 5-alkylimino-substituted uracils, and the reaction was promoted in the
presence of LiH (Table 1). Therefore, the more stable nitrenium ion D could be favorably formed and
attacked by the lone pair of the 6-imino nitrogen atom, the nucleophilicity of which would be enhanced
under the basic conditions.

HETEROCYCLES, Vol. 79, 2009
673
O
O
Me
CH NR
Me
O
CH NR
PhI(OAc)2
N
N
2
Ph
–OAc
NH
O
N
N I
N
H
OAc
Me
Me
PhI
PhI
A
C
3
O
O
O
N
Me
O
CH NHR
Me
O
CH NR
I
Me
O
CH NR
PhI(OAc)2
N
N
N
–OAc
NH
OAc
N
NH
N
NH
Ph
Me
Me
Me
6
B
D
Scheme 2. Plausible reaction mechanism
CONCLUSION
We have developed
a
facile synthetic method for the construction of
a
variety of
pyrazolo[2,3-d]pyrimidine and isoxazolo[2,3-d]pyrimidine derivatives by the iodobenzene
diacetate-promoted oxidative N–N or N–O bond formation. The oxidant is relatively less toxic and
produces no hazardous inorganic wastes. Since such fused pyrimidine analogs have recently attracted
attention as target molecules for drug development, the present study would offer a facile and safe
synthetic approach to potential bioactive compounds.
EXPERIMENTAL
General Methods. Unless otherwise stated, the commercially obtained materials were used without
further purification. The 1H NMR spectra were recorded by a JEOL JNM EX-400 spectrometer. Chemical
shifts (δ) are expressed in ppm and internally referenced (0.00 ppm for tetramethylsilane-CDCl3 and 2.49
ppm for DMSO-d6). The EI mass spectra were obtained using a JEOL JMS-SX102A instrument. The
elemental analyses were performed by a YANACO MT-5 instrument. The flash column chromatography
was performed using Kanto Chemical Co., Inc., silica gel 60N, spherical neutral (63-210 µm).
Synthesis of substrate:
General preparation method of 6-amino-5-[(substituted)-iminomethyl]-1,3-dimethyluracil
derivatives
(2a–2m).
To
a
suspension
of
5-[(dimethylamino)methylene]dihydro-6-imino-1,3-dimethylpyrimidine-2,4(1H,3H)-dione hydrochloride

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HETEROCYCLES, Vol. 79, 2009
(1) (2.47 g, 10.0 mmol) in dry DMF (70 mL) was dropwise added an amine (21.0 mmol). After stirring at
rt for 12 h, the mixture was concentrated in vacuo. The residue was triturated with Et2O (20 mL), and the
resulting precipitate was collected on a Kiriyama funnel and then recrystallized from EtOH.
6-Amino-1,3-dimethyl-5-[(phenylimino)methyl]uracil (2a)29: Aniline (1.0 mL, 11.0 mmol) and Et3N
(1.5 mL, 10.8 mmol) were added to a suspension of 1 (2.47 g, 10.0 mmol) in DMF (20 mL). mp
259–160 °C. 1H NMR (DMSO-d6) δ 3.22 (3H, s), 3.39 (3H, s), 7.27 (5H, m), 8.34 (1H, br s), 8.76 (1H, s),
11.11 (1H, br s). MS (EI) m/z: 258 (M+). Anal. Calcd for C13H14N4O2: C, 60.45; H, 5.46; N, 21.70. Found:
C, 60.64; H, 5.55; N, 21.67.
6-Amino-5-[{(4-fluorophenyl)imino}methyl]-1,3-dimethyluracil (2b)17: mp 288–290 °C (recrystallized
from EtOH). 1H NMR (DMSO-d6) δ 3.17 (3H, s), 3.35 (3H, s), 7.16 (2H, m), 7.17 (2H, m), 8.31 (1H, br
s), 8.68 (1H, s), 10.99 (1H, br s). MS (EI) m/z: 276 (M+). Anal. Calcd for C13H13FN4O2: C, 56.50; H, 4.75;
N, 20.29. Found: C, 56.33; H, 4.72; N, 20.30.
6-Amino-5-[{(4-chlorophenyl)imino}methyl]-1,3-dimethyluracil (2c)17: mp 258–259 °C (recrystallized
from EtOH). 1H NMR (CDCl3) δ 3.39 (3H, s), 3.49 (3H, s), 5.50 (1H, br s), 7.10 (2H, d, J = 8.8 Hz), 7.31
(2H, d, J = 8.8 Hz), 8.80 (1H, s), 11.95 (1H, br s). MS (EI) m/z: 292 (M+). Anal. Calcd for C13H13ClN4O2:
C, 53.34; H, 4.48; N, 19.14. Found: C, 53.48; H, 4.59; N, 19.22.
6-Amino-5-[{(3-chlorophenyl)imino}methyl]-1,3-dimethyluracil
(2d)17:
mp
265–267
°C
1
(recrystallized from EtOH). H NMR (DMSO-d6) δ 3.18 (3H, s), 3.36 (3H, s), 7.10 (1H, d, J = 8.3 Hz),
7.15–7.22 (2H, m), 7.38 (1H, t, J = 8.3 Hz), 8.38 (1H, br s), 8.70 (1H, s), 10.90 (1H, br s). MS (EI) m/z:
292 (M+). Anal. Calcd for C13H13ClN4O2: C, 53.34; H, 4.48; N, 19.14. Found: C, 53.15; H, 4.46; N,
19.21.
6-Amino-1,3-dimethyl-5-[{(3-nitrophenyl)imino}methyl]uracil (2e)17: mp >300 °C. 1H NMR
(DMSO-d6) δ 3.19 (3H, s), 3.37 (3H, s), 7.59–7.66 (2H, m), 7.92 (1H, s), 7.96–8.01 (1H, m), 8.46 (1H, br
s), 8.79 (1H, s), 10.87 (1H, br s). MS (EI) m/z: 303 (M+). Anal. Calcd for C13H13N5O4: C, 51.48; H, 4.32;
N, 23.09. Found: C, 51.25; H, 4.33; N, 23.08.
6-Amino-5-[{(4-methoxyphenyl)imino}methyl]-1,3-dimethyluracil
(2f)17:
mp
212–214
°C
1
(recrystallized from EtOH). H NMR (CDCl3) δ 3.38 (3H, s), 3.48 (3H, s), 3.82 (3H, s), 5.54 (1H, br s),
6.91 (2H, d, J = 8.8 Hz), 7.14 (2H, d, J = 8.8 Hz), 8.86 (1H, s), 12.23 (1H, br s). MS (EI) m/z: 288 (M+).
Anal. Calcd for C14H16N4O3: C, 58.32; H, 5.59; N, 19.44. Found: C, 58.17; H, 5.56; N, 19.38.
1
6-Amino-1,3-dimethyl-5-[(1-naphthalenylimino)methyl]uracil (2g)17: mp 275–278 °C. H NMR
(CDCl3) δ 3.41 (3H, s), 3.54 (3H, s), 5.64 (1H, br s), 7.12 (1H, d, J = 7.8 Hz), 7.43–7.55 (3H, m), 7.69
(1H, d, J = 8.3 Hz), 7.86 (1H, d, J = 8.3 Hz), 8.17 (1H, d, J = 7.8 Hz), 8.99 (1H, s), 12.25 (1H, br s). MS
(EI) m/z: 308 (M+). Anal. Calcd for C17H16N4O2: C, 66.22; H, 5.23; N, 18.17. Found: C, 66.12; H, 5.27; N,
18.13.

HETEROCYCLES, Vol. 79, 2009
675
6-Amino-1,3-dimethyl-5-[(methylimino)methyl]uracil (2h)29: mp 232–233 °C (recrystallized from
MeOH). 1H NMR (CDCl3) δ 3.28 (3H, s), 3.32 (3H, s), 3.36 (3H, s), 8.33 (1H, s). MS (EI) m/z: 196 (M+).
HRMS (EI) Calcd for C8H12N4O2 (M+) 196.0960. Found 196.0972.
1
6-Amino-5-[(t-butylimino)methyl]-1,3-dimethyluracil (2i): mp 186 °C. H NMR (CDCl3) δ 1.39 (9H,
s), 3.32 (3H, s), 3.33 (3H, s), 8.39 (1H, s). MS (EI) m/z: 238 (M+). Anal. Calcd for C11H18N4O2: C, 55.45;
H, 7.61; N, 23.51. Found: C, 55.22; H, 7.52; N, 23.25.
6-Amino-5-[(butylimino)methyl]-1,3-dimethyluracil (2j)31: n-Butylamine hydrochloride (1.22 g, 11.0
mmol) and Et3N (1.5 mL, 10.8 mmol) were added to a suspension of 1 (2.47 g, 10.0 mmol) in DMF (50
mL). mp 171–172 °C. 1H NMR (CDCl3) δ 0.95 (3H, t, J = 7.0 Hz), 1.40 (2H, m), 1.62 (2H, m), 3.32 (3H,
s), 3.35 (3H, s), 3.46 (2H, t, J = 7.0 Hz), 6.30 (1H, br s), 8.30 (1H, s), 11.90 (1H, br s). MS (EI) m/z: 238
(M+). Anal. Calcd for C11H18N4O2: C, 55.45; H, 7.61; N, 23.51. Found: C, 55.20; H, 7.52; N, 23.41.
6-Amino-5-[(cyclopentylimino)methyl]-1,3-dimethyl uracil (2k): Cyclopentylamine (0.12 mL, 2.4
mmol) and LiH (11.9 mg, 3.0 mmol) were added to a suspension of 1 (493 mg, 2 mmol) in DMF (10 mL).
After 3 h, the mixture was concentrated in vacuo and the residue was extracted using H2O (10 mL) and
CH2Cl2 (10 mL × 2). The combined organic layers were successively washed with H2O (20 mL) and
brine (20 mL), dried over MgSO4, and concentrated in vacuo. The residue was triturated with Et2O (10
1
mL) and the resulting precipitate was collected on a Kiriyama funnel. mp 212 °C. H NMR (CDCl3) δ
1.60–1.79 (6H, m), 1.96–2.02 (2H, m), 3.32 (3H, s), 3.35 (3H, s), 3.84 (1H, m), 6.21 (1H, br s), 8.36 (1H,
s), 11.95 (1H, br s). MS (EI) m/z: 250 (M+). Anal. Calcd for C12H18N4O2: C, 57.58; H, 7.25; N, 22.38.
Found: C, 57.39; H, 7.30; N, 22.30.
6-Amino-5-[(cyclohexylimino)methyl]-1,3-dimethyluracil (2l): Cyclohexylamine hydrochloride (298
mg, 2.2 mmol) and Et3N (0.6 mg, 4.3 mmol) were added to a suspension of 1 (493 mg, 2 mmol) in DMF
(10 mL). After 1.5 h, the mixture was poured into H2O (10 mL). The resulting precipitate was collected
1
on a Kiriyama funnel. mp 178–179 °C. H NMR (CDCl3) δ 1.34–1.49 (4H, m), 1.58–1.64 (2H, m),
1.76–1.79 (2H, m), 1.91–1.94 (2H, m), 3.29 (1H, m), 3.32 (3H, s), 3.34 (3H, s), 6.33 (1H, br s), 8.34 (1H,
s), 12.03 (1H, br s). MS (EI) m/z: 264 (M+). Anal. Calcd for C13H20N4O2: C, 59.07; H, 7.63; N, 21.20.
Found: C, 59.13; H, 7.61; N, 21.21.
1
6-Amino-5-[(cyclohexylmethylimino)methyl]-1,3-dimethyluracil (2m): mp 186 °C. H NMR (CDCl3)
δ 0.97 (2H, m), 1.14–1.30 (3H, m), 1.54–1.75 (6H, m), 3.29 (2H, d, J = 6.3 Hz), 3.32 (3H, s), 3.35 (3H, s),
6.36 (1H, br s), 8.24 (1H, s), 11.95 (1H, br s). MS (EI) m/z: 278 (M+). Anal. Calcd for C14H22N4O2: C,
60.41; H, 7.97; N, 20.13. Found: C, 60.34; H, 7.87; N, 19.92.
General procedure for the intramolecular N–N bond formation (3a–3m). To a suspension of
6-amino-5-[(substituted)-iminomethyl]-1,3-dimethyluracil (1.94 mmol) in dry DMF (20 mL) was

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HETEROCYCLES, Vol. 79, 2009
dropwise added iodobenzene diacetate (2.49 g, 7.74 mmol). The mixture was stirred at 80 °C for a given
time and concentrated in vacuo. To the residue were added H2O (15 mL) and CHCl3 (15 mL) and the
layers were separated. The aqueous layer was extracted with CHCl3 (15 mL × 2). The combined organic
layers were successively washed with H2O (20 mL) and brine (20 mL), dried over MgSO4, and
concentrated in vacuo. The residue was triturated with Et2O (10 mL) and the resulting precipitate was
collected on a Kiriyama funnel and then recrystallized from MeOH.
5,7-Dimethyl-2-phenyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (3a)17: mp 288–291 °C
(recrystallized from MeOH). 1H NMR (CDCl3) δ 3.43 (3H, s), 3.61 (3H, s), 7.39 (1H, t, J = 7.8 Hz), 7.51
(2H, t, J = 7.8 Hz), 7.72 (2H, d, J = 7.8 Hz), 8.43 (1H, s). MS (EI) m/z: 256 (M+). Anal. Calcd for
C13H12N4O2: C, 60.93; H, 4.72; N, 21.87. Found: C, 60.88; H, 4.86; N, 22.08.
2-(4-Fluorophenyl)-5,7-dimethyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione
(3b)17:
mp
270–271 °C (recrystallized from EtOH). 1H NMR (CDCl3) δ 3.43 (3H, s), 3.60 (3H, s), 7.21 (2H, dd, J =
9.0, 8.5 Hz), 7.70 (2H, m), 8.36 (1H, s). MS (EI) m/z: 274 (M+). Anal. Calcd for C13H11FN4O2: C, 56.93;
H, 4.04; N, 20.43. Found: C, 56.80; H, 4.12; N, 20.21.
2-(4-Chlorophenyl)-5,7-dimethyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione
(3c)17:
mp
1
290–293 °C (recrystallized from EtOH). H NMR (CDCl3) δ 3.43 (3H, s), 3.60 (3H, s), 7.48 (2H, d, J =
9.0 Hz), 7.67 (2H, d, J = 9.0 Hz), 8.40 (1H, s). MS (EI) m/z: 290 (M+). Anal. Calcd for C13H11ClN4O2: C,
53.71; H, 3.81; N, 19.27. Found: C, 53.71; H, 3.81; N, 19.09.
2-(3-Chlorophenyl)-5,7-dimethyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione
(3d)17:
mp
286–288 °C. 1H NMR (CDCl3) δ 3.43 (3H, s), 3.61 (3H, s), 7.36 (1H, d, J = 8.1 Hz), 7.44 (1H, t, J = 8.1
Hz), 7.59 (1H, d, J = 8.1 Hz), 7.80 (1H, s), 8.43 (1H, s). MS (EI) m/z: 290 (M+). Anal. Calcd for
C13H11ClN4O2·3/5H2O: C, 51.79; H, 4.08; N, 18.58. Found: C, 51.72; H, 3.84; N, 18.67.
5,7-Dimethyl-2-(3-nitrophenyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (3e)17: mp >300 °C.
1H NMR (CDCl3) δ 3.44 (3H, s), 3.63 (3H, s), 7.72 (1H, t, J = 8.3 Hz), 8.07 (1H, dd, J = 8.3, 2.2 Hz),
8.24 (1H, dd, J = 8.3, 2.2 Hz), 8.54 (1H, s), 8.66 (1H, dd, J = 2.2, 2.2 Hz). MS (EI) m/z: 301 (M+). HRMS
(EI) Calcd for C13H11N5O4 (M+) 301.0811. Found 301.0795.
2-(4-Methoxyphenyl)-5,7-dimethyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione
(3f)17:
mp
1
260–262 °C. H NMR (CDCl3) δ 3.43 (3H, s), 3.60 (3H, s), 3.87 (3H, s), 7.01 (2H, d, J = 9.0 Hz), 7.61
(2H, d, J = 9.0 Hz), 8.31 (1H, s). MS (EI) m/z: 286 (M+). Anal. Calcd for C14H14N4O3: C, 58.74; H, 4.93;
N, 19.57. Found: C, 58.66; H, 4.97; N, 19.52.
5,7-Dimethyl-2-(1-naphthalenyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione
(3g)17:
mp
1
233–235 °C (recrystallized from MeOH). H NMR (CDCl3) δ 3.47 (3H, s), 3.62 (3H, s), 7.53–7.66 (4H,
m), 7.79 (1H, d, J = 8.1 Hz), 7.93–8.06 (2H, m), 8.30 (1H, s). MS (EI) m/z: 306 (M+). Anal. Calcd for
C17H14N4O2: C, 66.65; H, 4.61; N, 18.29. Found: C, 66.80; H, 4.62; N, 18.32.

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677
1
2,5,7-Trimethyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (3h)14: mp 206–207 °C. H NMR
(CDCl3) δ 3.39 (3H, s), 3.52 (3H, s), 3.94 (3H, s), 7.87 (1H, s). MS (EI) m/z: 194 (M+). HRMS (EI) Calcd
for C8H10N4O2 (M+) 194.0804. Found 194.0813.
2-t-Butyl-5,7-dimethyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (3i): 2i (238 mg, 1 mmol),
iodobenzene diacetate (1.29 g, 4 mmol), and LiH (15.9 mg, 2 mmol) were used. The residue from the
extracts was purified by column chromatography on silica gel (hexane/EtOAc, 3 : 1) to give 3i (131 mg,
56%). mp 171–172 °C. 1H NMR (CDCl3) δ 1.61 (s, 9H), 3.39 (3H, s), 3.54 (3H, s), 8.02 (1H, s). MS (EI)
m/z: 236 (M+). Anal. Calcd for C11H16N4O2: C, 55.92; H, 6.83; N, 23.71. Found: C, 55.86; H, 6.78; N,
23.61.
2-n-Butyl-5,7-dimethyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (3j): 2j (477 mg, 2 mmol),
iodobenzene diacetate (2.58 g, 8 mmol), and LiH (31.8 mg, 4 mmol) were used. The residue from the
extracts was purified by column chromatography on silica gel (hexane/EtOAc, 3 : 1) to give 3j (399 mg,
1
85%). mp 127–128 °C. H NMR (CDCl3) δ 0.96 (3H, t, J = 7.3 Hz), 1.34 (2H, m), 1.88 (2H, quint, J =
7.3 Hz), 3.39 (3H, s), 3.53 (3H, s), 4.12 (2H, t, J = 7.3 Hz), 7.89 (1H, s). MS (EI) m/z: 236 (M+). Anal.
Calcd for C11H16N4O2: C, 55.92; H, 6.83; N, 23.71. Found: C, 55.85; H, 6.76; N, 23.74.
2-Cyclopentyl-5,7-dimethyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (3k): 2k (125 mg, 0.5
mmol), iodobenzene diacetate (644 mg, 2 mmol), and LiH (8.0 mg, 1 mmol) were used. The residue from
the extracts was purified by column chromatography on silica gel (hexane/EtOAc, 3 : 1) to give 3k (89.3
mg, 72%). mp 137 °C. 1H NMR (CDCl3) δ 1.74 (2H, m), 1.89 (2H, m), 2.04 (2H, m), 2.18 (2H, m), 3.39
(3H, s), 3.52 (3H, s), 4.64 (1H, m), 7.93 (1H, s). MS (EI) m/z: 248 (M+). Anal. Calcd for C12H16N4O2: C,
58.05; H, 6.50; N, 22.57. Found: C, 58.01; H, 6.46; N, 22.60.
2-Cyclohexyl-5,7-dimethyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (3l): 2l (132 mg, 0.5
mmol), iodobenzene diacetate (403 g, 1.25 mmol), and LiH (8.0 mg, 2 mmol) were used. The residue
from the extracts was purified by column chromatography on silica gel (CHCl3) to give 3l (89.2 mg,
68%). mp 172 °C. 1H NMR (CDCl3) δ 1.29 (1H, m), 1.44 (2H, m), 1.65–1.78 (3H, m), 1.93 (2H, m), 2.20
(2H, m), 3.39 (3H, s), 3.53 (3H, s), 4.09 (1H, m), 7.93 (1H, s). MS (EI) m/z: 262 (M+). Anal. Calcd for
C13H18N4O2: C, 59.53; H, 6.92; N, 21.35. Found: C, 59.50; H, 7.01; N, 21.38.
2-Cyclohexylmethyl-5,7-dimethyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (3m): 2m (139
mg, 0.5 mmol), iodobenzene diacetate (644 mg, 2 mmol), and LiH (8.0 mg, 1 mmol) were used. The
residue from the extracts was purified by column chromatography on silica gel (hexane/EtOAc, 3 : 1) to
1
give 3m (92.1 mg, 67%). mp 161–162 °C. H NMR (CDCl3) δ 0.97 (2H, m), 1.20–1.26 (4H, m),
1.72–1.75 (4H, m), 1.93 (1H, m), 3.39 (3H, s), 3.53 (3H, s), 3.93 (2H, d, J = 7.0 Hz), 7.84 (1H, s). MS
(EI) m/z: 276 (M+). Anal. Calcd for C14H20N4O2: C, 60.85; H, 7.29; N, 20.27. Found: C, 60.86; H, 7.35; N,
20.32.

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General procedure for the intramolecular N–O bond formation (5a–5c). To a suspension of
5-acyl-6-amino-1,3-dimethyluracil (4a–4c) (1 mmol) in dry DMF (5 mL) were dropwise added
iodobenzene diacetate (805 g, 2.5 mmol) and LiH (15.9 mg, 2 mmol). The mixture was stirred at 80 °C
for a given time and concentrated in vacuo. To the residue were added H2O (15 mL) and CHCl3 (15 mL)
and the layers were separated. The aqueous layer was extracted with CHCl3 (15 mL × 2). The combined
organic layers were successively washed with H2O (20 mL) and brine (20 mL), dried over MgSO4, and
concentrated in vacuo. The residue was then purified by column chromatography on silica gel (CHCl3).
1
3,5,7-Trimethylisoxazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (5a)18: mp 201 °C. H NMR (CDCl3) δ
2.75 (3H, s), 3.37 (3H, s), 3.49 (3H, s). MS (EI) m/z: 195 (M+). HRMS (EI) Calcd for C8H9N3O3 (M+)
195.0644. Found 195.0635.
3-Ethyl-5,7-dimethylisoxazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (5b)18: mp 91 °C. 1H NMR
(CDCl3) δ 1.38 (3H, t, J = 7.8 Hz), 3.13 (2H, q, J = 7.8 Hz), 3.36 (3H, s), 3.48 (3H, s). MS (EI) m/z: 209
(M+). Anal. Calcd for C9H11N3O3: C, 51.67; H, 5.30; N, 20.09. Found: C, 51.55; H, 5.24; N, 19.83.
5,7-Dimethyl-3-propylisoxazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (5c)18: mp 43 °C. 1H NMR
(CDCl3) δ 1.00 (3H, t, J = 7.6 Hz), 1.83 (2H, m), 3.07 (2H, t, J = 7.6 Hz), 3.34 (3H, s), 3.47 (3H, s). MS
(EI) m/z: 223 (M+). Anal. Calcd for C10H13N3O3: C, 53.81; H, 5.87; N, 18.82. Found: C, 53.89; H, 5.76; N,
18.57.
REFERENCES
¶ Current address: School of Pharmacy, Aichi Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku,
Nagoya 464-8650, Japan
1. R. K. Robins, J. Am. Chem. Soc., 1956, 78, 784; P. Feigelson, J. D. Davidson and R. K. Robins, J.
Biol. Chem., 1957, 226, 993; S. Kobayashi, Chem. Pharm. Bull., 1973, 21, 941; R. K. Robins, G. R.
Revankar, D. E. O’Brien, R. H. Springer, T. Novinson, A. Albert, K. Senga, J. P. Miller, and D. G.
Streeter, J. Heterocycl. Chem., 1985, 22, 601.
2. M. H. Elnagdi and M. R. H. Elmoghayar, 'Advances in Heterocyclic Chemistry: Chemistry of
Pyrazolopyrimidines,' Vol. 41, ed. by A. R. Katritzky, Academic Press, Orlando, 1987, pp. 319–376;
J. V. Greehill, 'Comprehensive Heterocyclic Chemistry: Pyrazoles with Fused Six-menmbered
Heterocyclic Rings,' Vol. 5, eds. by A. R. Katritzky and C. W. Rees, Pergamon Press, Oxford, 1984,
pp. 305–343.
3. R. K. Robins, J. Med. Chem., 1964, 7, 186; C. R. Petrie III, H. B. Cottam, P. A. McKernan, R. K.
Robins, and G. H. Revankar, J. Med. Chem., 1985, 28, 1010.
4. J. H. Hanke, J. P. Gardner, R. L. Dow, P. S. Changelian, W. H. Brissette, E. J. Weringer, B. A.
Pollok, and P. A. Connelly, J. Biol. Chem., 1996, 271, 695; T. Maruyama, Y. Yamamoto, A.

HETEROCYCLES, Vol. 79, 2009
679
Shimizu, H. Masuda, N. Sakai, R. Sakurai, H. Asada, and Y. Yoshimura, Biol. Reprod., 2004, 70,
214; F. Carraro, A. Pucci, A. Naldini, S. Schenone, O. Bruno, A. Ranise, F. Bondavalli, C. Brullo, P.
Fossa, G. Menozzi, L. Mosti, F. Manetti, and M. Botta, J. Med. Chem., 2004, 47, 1596.
5. F. Carraro, A. Naldini, A. Pucci, G. A. Locatelli, G. Maga, S. Schenone, O. Bruno, A. Ranise, F.
Bondavalli, C. Brullo, P. Fossa, G. Menozzi, L. Mosti, M. Modugno, C. Tintori, F. Manetti, and M.
Botta, J. Med. Chem., 2006, 49, 1549; F. Manetti, A. Santucci, G. A. Locatelli, G. Maga, A.
Spreafico, T. Serchi, M. Orlandini, G. Bernardini, N. P. Caradonna, A. Spallarossa, C. Brullo, S.
Schenone, O. Bruno, A. Ranise, F. Bondavalli, O. Hoffmann, M. Bologna, A. Angelucci, and M.
Botta, J. Med. Chem., 2007, 50, 5579.
6. P. Traxler and P. Furet, Pharmacol. Ther., 1999, 82, 195.
7. F. Manetti, C. Brullo, M. Magnani, F. Mosci, B. Chelli, E. Crespan, S. Schenone, A. Naldini, O.
Bruno, M. L. Trincavelli, G. Maga, F. Carraro, C. Martini, F. Bondavalli, and M. Botta, J. Med.
Chem., 2008, 51, 1252.
8. J. Das, R. V. Moquin, S. Pitt, R. Zhang, D. R. Shen, K. W. McIntyre, K. Gillooly, A. M. Doweyko, J.
S. Sack, H. Zhang, S. E. Kiefer, K. Kish, M. McKinnon, J. C. Barrish, J. H. Dodd, G. L. Schieven,
and K. Leftheris, Bioorg. Med. Chem. Lett., 2008, 18, 2652.
9. I. Devesa, M. J. Alcaraz, R. Riguera, and M. L. Ferrándiz, Eur. J. Pharmacol., 2004, 488, 225.
10. A. Ali, G. E. Taylor, K. Ellsworth, G. Harris, R. Painter, L. L. Silver, and K. Young, J. Med. Chem.,
2003, 46, 1824.
11. Y. Zhang, G. Jin, B. Illarionov, A. Bacher, M. Fischer, and M. Cushman, J. Org. Chem., 2007, 72,
7176.
12. R. J. Gillespie, I. A. Cli, C. E. Dawson, C. T. Dourish, S. Gaur, A. M. Jordan, A. R. Knight, J.
Lerpiniere, A. Misra, R. M. Pratt, J. Ro, G. C. Stratton, R. Upton, S. M. Weiss, and D. S. Williamson,
Bioorg. Med. Chem. Lett., 2008, 18, 2924.
13. H. Liu, X. He, H.-S. Choi, K. Yang, D. Woodmansee, Z. Wang, D. A. Ellis, B. Wu, Y. He, and T. N.
Nguyen (Irm LLC, Bermuda), PCT Int. Appl., WO2006047516; Chem. Abstr., 2006, 144, 450725.
14. S. Senda, K. Hirota, and G.-N. Yang, Chem. Pharm. Bull., 1972, 20, 391
15. For example: T. Higashino, Y. Iwai, and E. Hayashi, Chem. Pharm. Bull., 1976, 24, 3120; R.
Madroñero and S. Vega, Synthesis, 1987, 628; J. Garín, M. P. Loscertales, E. Meléndez, F. L.
Merchán, R. Rodriguez, and T. Tejero, Heterocycles, 1987, 26, 1303; P. Molina, A. Argues, and M.
V. Vinader, Tetrahedron Lett., 1987, 28, 4451; P. Molina, A. Argues, M. V. Vinader, J. Becher, and
K. Brondum, J. Org. Chem., 1988, 53, 4654; R. S. Hosmane and B. B. Lim, Synthesis, 1988, 242; J.
D. Anderson, H. B. Cottam, S. B. Larson, L. D. Nord, G. R. Revankar, and R. K. Robins, J.
Heterocycl. Chem., 1990, 27, 439; P. Molina, A. Argues, and M. V. Vinader, Synthesis, 1990, 469; S.

680
HETEROCYCLES, Vol. 79, 2009
Guccione, L. M. Scolaro, and F. Russo, J. Heterocycl. Chem., 1996, 33, 459.
16. For example: S. Senda, K. Hirota, and G.-N. Yang, Chem. Pharm. Bull., 1972, 20, 399; K. Senga, Y.
Kanamori, H. Kanazawa, and S. Nishigaki, Synthesis, 1977, 176; F. Yoneda, T. Nagamatsu, and T.
Nagamura, J. Chem. Soc., Perkin Trans. 1, 1977, 765; K. Senga, Y. Kanamori, H. Kanazawa, and S.
Nishigaki, J. Heterocycl. Chem., 1978, 15, 359; P. Mátyus, P. Sohár, and H. Wamhoff, Heterocycles,
1984, 22, 513; A. M. El-Reedy, A. S. Ali, and A. O. Ayyad, J. Heterocycl. Chem., 1989, 26, 313; P.
Bhuyan, R. C. Boruah, and J. S. Sandhu, J. Org. Chem., 1990, 55, 568; R. Neidlein and Z. Wang,
Heterocycles, 1997, 45, 1509.
17. Preliminary results were reported as a communication; H. Sajiki, K. Hattori, M. Sako, and K. Hirota,
Synlett, 1997, 1409.
18. R. Marumoto and Y. Furukawa, Chem. Pharm. Bull., 1977, 25, 2974.
19. S. Nishigaki, Y. Kanamori, and K. Senga, Chem. Pharm. Bull., 1978, 26, 2497; F. Yoneda, T. Yano,
M. Higuchi, and A. Koshiro, Chem. Lett., 1978, 155.
20. K. Hirota, K. Maruhashi, T. Asao, N. Kitamura, Y. Maki, and S. Senda, Chem. Pharm. Bull., 1983,
31, 3959.
21. D. V. Tinh and W. Stadlbauer, J. Heterocycl. Chem., 1966, 33, 1025.
22. N. Matsumoto and M. Takahashi, Tetrahedron, 2002, 58, 10073.
23. P. J. Stang and V. V. Zhdankin, Chem. Rev., 1996, 96, 1123; T. Wirth and U. H. Hirt, Synthesis,
1999, 1271.
24. A. Kotali and P. A. Harris, J. Heterocycl. Chem., 1996, 33, 605.
25. A. Correa, I. Tellitu, E. Domínguez, and R. SanMartin, J. Org. Chem., 2006, 71, 3501.
26. O. Prakash, R. K. Saini, S. P. Singh, and R. S. Varma, Tetrahedron Lett., 1997, 38, 3147; A. C. S.
Reddy, B. Narsaiah, and R. V. Venkataratnam, Synth. Commun., 1997, 27, 2217.
27. K. Hirota, Y. Kitade, H. Sajiki, and Y. Maki, Synthesis, 1984, 589.
28. K. Hirota, K. Kubo, H. Sajiki, Y. Kitade, M. Sako, and Y. Maki, J. Org. Chem., 1997, 62, 2999.
29. The cyclization precursors 2a and 2h could also be obtained by the reaction of the 5-foymyl- or
5-thioformyl-6-amino-1,3-dimethyluracil derivatives with primary amines. K. Hirota, K. Kubo, and
H. Sajiki, Chem. Pharm. Bull., 1997, 45, 542.
30. G. P. Ford and J. D. Scribner, J. Am. Chem. Soc., 1981, 103, 4281; A. Ohwada, S. Nara, T.
Sakamoto, and Y. Kikugawa, J. Chem. Soc., Perkin Trans. 1, 2001, 3064; Y. Kikugawa, A.
Nagashima, T. Sakamoto, E. Miyazawa, and M. Shiiya, J. Org. Chem., 2003, 68, 6739.
31. J. Clark and M. S. Morton, J. Chem. Soc., Perkin Trans. 1, 1974, 1812.