An efficient synthesis of 6,9-disubstituted purin-8-ones via copper-catalyzed coupling/cyclization

Article abstract of DOI:10.1016/j.tet.2010.04.106

An efficient and novel synthesis of 6,9-disubstituted purin-8-ones has been developed. Starting from dichloropyrimidin-5-ylcarbamate, CuCl/amino acid catalyzed coupling/cyclization reaction with amines was achieved to afford 9-substituted 6-chloropurin-8-ones. Then a microwave-assisted amination procedure was carried out for the synthesis of 6,9-disubstituted purin-8-ones in moderate to good yields.

Full text of DOI:10.1016/j.tet.2010.04.106

Tetrahedron 66 (2010) 5107e5111
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
An efficient synthesis of 6,9-disubstituted purin-8-ones via copper-catalyzed
coupling/cyclization
*
Qi-Fei Zhong, Li-Ping Sun
Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and novel synthesis of 6,9-disubstituted purin-8-ones has been developed. Starting from
dichloropyrimidin-5-ylcarbamate, CuCl/amino acid catalyzed coupling/cyclization reaction with amines
was achieved to afford 9-substituted 6-chloropurin-8-ones. Then a microwave-assisted amination pro-
cedure was carried out for the synthesis of 6,9-disubstituted purin-8-ones in moderate to good yields.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 6 January 2010
Received in revised form 25 March 2010
Accepted 27 April 2010
Available online 28 May 2010
Keywords:
Purin-8-ones
Copper-catalyzed coupling/cyclization
Microwave-assisted synthesis
1. Introduction
Me
O
N
NH2
N
N
Purine derivatives constitute an enormous class of compounds,
some of which are well-known as therapeutic agents. These fused
planar heterocycles present key hydrogen bond donating/accepting
functionalities, making them interesting scaffolds for targeting
many biosynthetic, regulatory and signal transduction proteins
including cellular kinases, G proteins, and polymerases.1 Purinones
are derivatives of purine, such as purin-8-one or 8-hydroxypurine
derivatives reported to possess a wide range of biological activities.
As described in Figure 1, 9-aryl-purin-8-one 1 has an excellent
binding affinity to the corticotropin-releasing hormone (CRH) re-
ceptor, a key player in anxiety related disorders.2 Others stimulate
the humoral immune responses by binding selectively to B-cells.3
8-Hydroxypurine derivatives 2 and 3 were also reported as
potent interferon-inducing agents for treatment of hepatitis C,4 or
as cyclin-dependent kinases (CDKs) inhibitors by binding to the
ATP pockets of the proteins.5 Especially the 6,9-diaryl purin-8-one
4 and its derivatives were reported to possess strong p38 MAP
kinase inhibiting activities.6 Accordingly, the development of more
efficient, convenient and environmentally friendly methods for the
synthesis of 6,9-disubstituted purin-8-ones is extremely necessary.
Three approaches were reported for the construction of purin-
8-one skeleton. The first way is the modification of adenine or
guanine derivatives.7 The second route involves the construction
of the fused heterocyclic skeleton via the useful intermediate
N
N
N
OH
Me
N
Me
Me
N
HN
Me
N
MeO
Me
1
2
H
N
HN
N
N
O
F
N
N
N
N
OH
HN
N
F
HO
3
4
Figure 1. Examples of biologically active purinones.
1-substituted 5-amino-4-cyano-2-oxoimidazole.8 Still there are
several problems associated with these methodologies, including
long synthetic routes,7b the long reaction times required,9 and,
more significantly, in some cases, the poor yields reported.10 As
a third alternative, purin-8-one derivatives can be synthesized
through the classical method that involves nucleophilic displace-
ment of ortho-nitro substituted pyrimidinyl halides with amines
and subsequent reduction and cyclization with carbon-
yldiimidazole or triphosgene,11 which is the limitation of the
diversity of the products because of the commercial unavailability
of the key reagent of ortho-nitro substituted pyrimidinyl halides.
These drawbacks had prompted Kuethe and co-workers to develop
* Corresponding author. Tel./fax: þ86 25 83271351; e-mail address: chslp@cpu.
edu.cn (L.-P. Sun).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.106

5108
Q.-F. Zhong, L.-P. Sun / Tetrahedron 66 (2010) 5107e5111
a
Palladium-catalyzed aryl amination strategy leading to
trans-4-hydroxy-L-proline (40 mol %) as the ligand and K2CO3
substituted imidazo[4,5-b]pyridin-2-ones but obtained low
yields.12In recent years, copper-catalyzed CeN coupling reactions
have been reported to be used extensively for the synthesis of
heterocycles in good yields,13 including benzimidazol-2-one rela-
tives,14 which is much similar to purin-8-ones, for example, several
groups have reported the synthesis of 1,3-dihydrobenzimidazol-2-
ones by using CuI-catalyzed intramolecular cyclization very
recetenly,14aed However, copper-catalyzed synthesis of purin-8-one
skeletons has not been seen in literatures as yet. As a part of our
continuing effort to assemble heterocycles by copper-catalyzed
cross-coupling reactions,15 we are interested in developing a novel
protocol for the construction of purin-8-one skeleton. Here we
disclose an efficient synthesis of 6,9-disubstituted purin-8-ones via
copper-catalyzed coupling/cyclization process.
(2 equiv) as the base in DMSO at 70e130 ꢀC. Three commercially
available cuprous salts were evaluated for the coupling reaction,
and among them, the catalyst of CuCl gave the most promising
result. Heating a mixture of dichloropyrimidin-5-ylcarbamate 5
and amine 6a together with CuI catalyst in the presence of 40 mol %
trans-4-hydroxy-L
-proline in DMSO at 70e130 ꢀC afforded the
expected purin-8-one skeleton 7a in 56% yield (Table 1, entry 5).
When CuBr was used, the yield was increased to 65% (Table 1, entry
6), while the best yield was observed when CuCl was employed
(81%, Table 1, entry 7). It was demonstrated that certain cuprous
salts play important roles for rate accelerations in the cross-cou-
pling reaction. The amino-acid ligands are thought to increase
catalyst solubility and stability and to prevent aggregation of the
metal.19 It was clear that the optimized reaction condition was to
use 20 mol % CuCl in combination of 40 mol % trans-4-hydroxy-L-
proline as the ligand, K2CO3 as the base and DMSO as the solvent.
To explore the scope and limits of the coupling reaction of
dichloropyrimidin-5-ylcarbamate 5 with amines, other amines
6bee were tested under the above optimized conditions, and the
results are summarized in Table 2. We were pleased to find that
aliphatic amines worked well for this reaction (Table 2, entries
1e4), but it was failed with aromatic amines (Table 2, entry 5), even
under microwave irradiation. For the cyclization reaction, sterically
hindered amines generally required longer reaction times (Table 2,
entry 4).
2. Results and discussion
Initially we tried to get methyl (4,6-dichloropyrimidin-5-yl)
carbamate16 starting from 4,6-dichloropyrimidin-5-amine,
un-
17
fortunately, the very low yield of the carbamate product was pro-
vided. Then we synthesized dichloropyrimidin-5-ylcarbamate 5
according to an efficient procedure described by Gerhard and Felix
in
3
steps,18 which then underwent the copper-catalyzed
coupling/cyclization reaction with amines in order to afford the
target 9-substituted 6-chloropurin-8-ones 7 (Scheme 1).
Table 2
Cl
Cl
N
H
N
Synthesis of 9-substituted 6-chloropurin-8-ones 7aeea
H
N
CuX/Ligand
N
OMe
BnNH2
O
N
Entry
1
Amine
Product
Yieldb (%)
81
N
Bn
Base, DMSO
N
O
Cl
Cl
H
N
5
6a
7a
N
BnNH2
6a
7a
O
N
N
Scheme 1.
Bn
Cl
As shown in Table 1, the model coupling/cyclization reaction of 5
with benzylamine 6a was conducted under the action of 20 mol %
H
N
N
N
N
O
O
O
2
3
6b
6c
7b
7c
62
77
NH2
NH2
of CuI, 40 mol % of L
-proline and K2CO3 in THF at 70 ꢀC. It was found
N
that after 24 h most of 5 was consumed, and only the cross-cou-
pling product was identified, indicating that the condensative
cyclization reaction maybe required higher reaction temperatures.
After some trials, we found that the desired cyclization product 7a
could be obtained in moderate yield under the high reaction tem-
perature in DMSO for 3 h after the initial cross-coupling step (Table
1, entry 1). This result was consistent with that reported by Ma.14a
Switching the base to Cs2CO3 or K3PO4 provided a fairly poor result
(Table 1, entries 2 and 3), while the cross-coupling reaction was
failed when K3PO4 was used as the base and dmeda (N,N0-dime-
thylethanediamine) as the ligand (Table 1, entry 4). trans-4-Hy-
Cl
H
N
O
Ph
N
N
Cl
H
N
N
N
O
O
4
6d
6e
7d
7e
84c
NH2
NH2
N
Cl
N
H
N
N
droxy-L-proline was obviously efficient than L-proline as a ligand
(Table 1, entry 5). We then carried out copper catalyst screen using
5
0
N
a
Table 1
Reaction conditions: chloride
5
(0.5 mmol), amine
6 (0.55 mmol), CuCl
Synthesis of N-benzyl-6-chloropurin-8-one 7aa
(0.1 mmol), trans-4-hydroxy-
L-proline (0.2 mmol), K2CO3 (1.0 mmol), DMSO
(2.5 mL), 70 ꢀC, 1 h, then 130 ꢀC, 3 h.
Entry
CuX
Ligand
Base
Yieldb (%)
b
Isolated yield.
c
Reaction was conducted at 70 ꢀC for 1 h, and then 130 ꢀC for 5 h.
1
2
3
4
5
6
7
8
9
CuI
CuI
CuI
L
L
L
-proline
-proline
-proline
K2CO3
Cs2CO3
K3PO4
K3PO4
K2CO3
K2CO3
K2CO3
K3PO4
K2CO3
41
20
22
0
56
65
81
48
63
Finally, we examined the amination reaction of 7 in order to
obtain a number of structurally diverse purin-8-ones 8 (Scheme 2).
It was initially observed that the reaction of 7a with 1.2 equiv ani-
line occurred slowly, and after refluxing for 12 h in the presence of
concd HCl in n-BuOH, only 79% yield of 8a was afforded. However,
performing the reaction with aniline under microwave irradiation
at 120 ꢀC dramatically decreased the reaction time from 12 h to
40 min,20 and the yield was increased to 90% (Table 3, entry 1). We
also found that EtOH was better than n-BuOH as a solvent. Initially,
CuI
Dmeda
CuI
trans-4-Hydroxy-
trans-4-Hydroxy-
trans-4-Hydroxy-
trans-4-Hydroxy-
L-proline
L-proline
L-proline
L-proline
CuBr
CuCl
CuCl
CuCl
L
-proline
a
Reaction conditions: chloride
5 (0.5 mmol), amine 6a (0.55 mmol), CuX
(0.1 mmol), ligand (0.2 mmol), base (1.0 mmol), DMSO (2.5 mL), 70 ꢀC, 1 h, then
130 ꢀC, 3 h.
b
Isolated yield.

Q.-F. Zhong, L.-P. Sun / Tetrahedron 66 (2010) 5107e5111
5109
R2
the same reaction conditions, but it provided a fairly poor yield
(Table 3, entry 7).
Cl
N
H
N
HN
N
N
H
R2NH2, EtOH, HCl (concd)
MW, 40 min
N
N
O
O
N
R1
N
R1
8a-o
3. Conclusion
7a-d
In conclusion, we have developed here an efficient and novel
synthesis of new 6,9-disubstituted purin-8-ones 8. Starting from
the readily available methyl (4,6-dichloropyrimidin-5-yl) carba-
Scheme 2.
Table 3
Synthesis of 6,9-disubstituted purin-8-ones 8aeoa
mate 5, CuCl/trans-4-hydroxy-L-proline catalyzed coupling and
subsequent cyclization reaction was carried out for the con-
struction of 9-substituted 6-chloropurin-8-ones. Introduction of
diversity in the position C-6 could be achieved by the microwave-
assisted amination reaction of 7 to afford 6,9-disubstituted purin-
8-one derivatives. Our synthesis is of interest for the generation of
purin-8-ones libraries with anti-tumor bioactivities. Work toward
this goal is currently in progress in our laboratory.
Entry
1
Product
R1
R2
Yieldb (%)
90
81c
8a
eBn
2
3
8b
8c
eBn
eBn
OCH3
Cl
74
4
5
8d
8e
eBn
eBn
92
39
F
4. Experimental section
4.1. General informations
Cl
F
1H NMR were recorded on a Bruker AV-300 spectrometer.
Chemical shifts are reported in parts per million related to the re-
sidual solvent from TMS as internal standard (scale). Multiplicity is
designated as singlet (s), doublet (d), doublet of doublet (dd), triplet
(t), multiplet (m), or broad singlet (br s). Infrared (IR) spectra were
taken on a Nicolet Impact 410 FT-IR spectro- photometer as KBr
pellets. Mass spectra (MS) were measured on a Finnigan Shimadzu
GCeMS mass spectrometer. Melting points were measured in a hot
stage microscope. Elemental analyses are within ꢁ0.5% of theo-
retical values and were done by China Pharmaceutical University.
All reactions were monitored by HPTLC using UV light. Column
chromatography was completed on silica gel (100e200 mesh)
made in Qingdao Haiyang Chemical Co. Ltd.
H3CO
6
8f
eBn
eBn
70
7
8
8g
8h
40
44
O
O
O
Cl
9
8i
8j
28
38
CH3
Cl
10
F
11
12
8k
8l
66
80
H3CO
4.2. Experimental details and spectroscopic data
13
14
8m
8n
74
56
4.2.1. Methyl (4,6-dichloropyrimidin-5-yl) carbamate (5)18. The
product was afforded by the procedure described by Gerhard and
Felix as a light yellow solid in 76% isolated yield. Mp 92e93 ꢀC; IR
Cl
(KBr): 3213, 1701, 1536, 1513, 1415, 1390 cmꢂ1 1H NMR (300 MHz,
;
H3CO
15
8o
41
CDCl3):
d 3.84 (s, 3H), 6.38 (s, 1H), 8.69 (s, 1H) ppm; MS (EI) m/z
221 (Mþ).
a
Reaction conditions: 7 (0.5 mmol), R2NH2 (0.6 mmol), concd HCl (50
mL), EtOH
General procedure A for the synthesis of 9-substituted 6-chlor-
opurin-8-ones 7aed from dichloropyrimidin-5-ylcarbamate 5: A two-
neck bottle was charged with dichloropyrimidin-5-ylcarbamate 5
(3 mL), microwaves, 120 ꢀC, 40 min.
b
Isolated yield.
c
Reaction was conducted in n-BuOH at 120 ꢀC for 40 min to afford 8b in 58% yield.
(110 mg, 0.5 mmol), CuCl (10 mg, 0.1 mmol), trans-4-hydroxy-L-
we chose n-BuOH as the solvent, 8b was afforded in 58% isolated
yield under microwave irradiation at 120 ꢀC for 40 min, while
a better yield was observed when EtOH was employed (Table 3,
entry 2).
proline (26 mg, 0.2 mmol), and K2CO3 (138 mg, 1.0 mmol), back-
filled with N2 atmosphere. Amine 6 (0.55 mmol) and DMSO
(2.5 mL) were successively added. The reaction mixture was stirred
at 70 ꢀC until the coupling was completed detected by TLC. The
solution was then heated at 130 ꢀC until the coupling product was
consumed monitored by TLC. The cold mixture was partitioned
between EtOAc (20 mL) and saturated NH4Cl (20 mL). The organic
layer was washed with brine (1ꢃ20 mL), dried over Na2SO4, and
concentrated in vacuo. The residue was purified by column chro-
matography on silica gel (EtOAc/petroleum ether 1:3) to provide
the desired product 7 (Table 2).
Under this optimized conditions, a number of 6,9-disubstituted
purin-8-ones were synthesized. As shown in Table 3, the anilines
bearing chloro-, methyl-, and methoxyl-substitutions were well
tolerated (Table 3, entries 2, 3, 6, 12, and 14), although those con-
taining an electron-withdrawing group typically gave lower yields
(Table 3, entries 5 and 10), para-fluoroaniline gave an exception
(Table 3, entry 4). No significant electronic effects were observed
for the ortho- and para-substituted anilines (Table 3, entries 2 and
6). Moreover, 9-(furan-2-ylmethyl) substituted derivatives were
afforded in relatively poor yields than other alkyl substituted ones
(Table 3, entries 8e10). Except for anilines, we also used aliphatic
amine such as cyclohexylamine for the amination reaction under
4.2.2. 9-Benzyl-6-chloro-7H-purin-8(9H)-one (7a). The general
procedure A was followed for the synthesis and purification giving
a light yellow solid in 81% isolated yield. Mp 250e251 ꢀC; IR (KBr):
3407, 1712, 1634, 1587, 1495, 733, 696 cmꢂ1 1H NMR (300 MHz,
;

5110
Q.-F. Zhong, L.-P. Sun / Tetrahedron 66 (2010) 5107e5111
DMSO-d6):
d
5.02 (s, 2H), 7.28e7.34 (m, 5H), 8.44 (s, 1H), 12.22 (br s,
Anal. Calcd for C18H14ON5F: C, 64.47; H, 4.21; N, 20.88. Found: C,
64.49; H, 4.14; N, 20.76.
1H) ppm; MS (EI) m/z 260 (Mþ).
4.2.3. 6-Chloro-9-(furan-2-ylmethyl)-7H-purin-8(9H)-one (7b). The
general procedure A was followed for the synthesis and purification
giving a light yellow solid in 62% isolated yield. Mp 217e218 ꢀC; IR
4.2.10. 9-Benzyl-6-(3-chloro-4-fluorophenylamino)-7H-purin-8
(9H)-one (8e). The general procedure B was followed for the syn-
thesis and purification giving a white solid in 39% isolated yield. Mp
318e320 ꢀC; IR (KBr): 3401, 3352, 1698, 1645, 1618, 1598, 1587,
1493, 1462, 1408, 806, 778, 747, 718, 698 cmꢂ1; 1H NMR (300 MHz,
(KBr): 3393, 1712, 1633, 1584, 1486 cmꢂ1 1H NMR (300 MHz,
;
CDCl3):
d 5.15 (s, 2H), 6.33e6.48 (m, 2H), 7.36 (s, 1H), 8.56 (s, 1H),
9.02 (s, 1H) ppm; MS (EI) m/z 250 (Mþ).
DMSO-d6):
d
4.99 (s, 2H), 7.25e7.48 (m, 7H), 8.06 (dd, J¼2.7, 2.4 Hz,
1H), 8.30 (s, 1H), 8.91 (s, 1H), 10.38 (br s, 1H) ppm; MS (EI) m/z 369
(Mþ). Anal. Calcd for C18H13ON5FCl: C, 58.47; H, 3.54; N, 18.94.
Found: C, 58.88; H, 3.83; N, 18.53.
4.2.4. 6-Chloro-9-phenethyl-7H-purin-8(9H)-one (7c). The general
procedure A was followed for the synthesis and purification giving
a light yellow solid in 77% isolated yield. Mp 204e205 ꢀC; IR (KBr):
3381, 1712, 1633, 1583, 1491, 733, 698 cmꢂ1
;
1H NMR (300 MHz,
4.2.11. 9-Benzyl-6-(2-methoxyphenylamino)-7H-purin-8(9H)-one
(8f). The general procedure B was followed for the synthesis and
purification giving an off-white solid in 70% isolated yield. Mp
274e276 ꢀC; IR (KBr): 3333, 3148, 1712, 1663, 1626, 1587, 1488,
DMSO-d6):
d
3.04 (t, J¼7.2 Hz, 2H), 4.06 (t, J¼7.2 Hz, 2H), 7.16e7.28
(m, 5H), 8.42 (s, 1H), 12.04 (br s, 1H) ppm; MS (EI) m/z 274 (Mþ).
4.2.5. 6-Chloro-9-cyclohexyl-7H-purin-8(9H)-one (7d). The general
procedure A was followed for the synthesis and purification giving
a light yellow solid in 84% isolated yield. Mp 252e254 ꢀC; IR (KBr):
1453, 747, 699 cmꢂ1; 1H NMR (300 MHz, DMSO-d6):
d 3.88 (s, 3H),
4.98 (s, 2H), 6.94 (t, J¼7.5 Hz, 1H), 7.04e7.06 (m, 2H), 7.30e7.34 (m,
5H), 8.08 (s, 1H), 8.14 (d, J¼7.5 Hz, 1H), 8.22 (s, 1H), 11.08 (s, 1H)
ppm; MS (EI) m/z 347 (Mþ). Anal. Calcd for C19H17O2N5: C, 65.69; H,
4.93; N, 20.16. Found: C, 65.83; H, 4.89; N, 19.94.
3415, 1708, 1631, 1574, 1478 cmꢂ1 1H NMR (300 MHz, DMSO-d6):
;
d
1.16e1.38 (m, 3H), 1.64e1.84 (m, 5H), 2.16e2.24 (m, 2H), 4.17 (t,
J¼9.0 Hz,1H), 8.43(s,1H),12.05(brs,1H) ppm; MS(EI) m/z252 (Mþ).
General procedure B for the synthesis of 6,9-disubstituted purin-
8-ones 8aeo: To a solution of 7 (0.5 mmol) in EtOH (3 mL) were
4.2.12. 9-Benzyl-6-(cyclohexylamino)-7H-purin-8(9H)-one
(8g).
The general procedure B was followed for the synthesis and puri-
added 12 M concd HCl (50
mL) and aniline or cyclohexylamine
fication giving a white solid in 40% isolated yield. Mp 244e246 ꢀC;
(0.60 mmol). The vial was sealed and heated by microwave at
120 ꢀC for 40 min. After cooling to rt, the obtained crystals were
collected by filtration and washed with cold EtOH to afford the pure
product 8 (Table 3).
IR (KBr): 3414, 3340, 1692, 1646, 1620, 1598, 1456, 699 cmꢂ1 1H
;
NMR (300 MHz, DMSO-d6): d 1.21e1.37 (m, 5H), 1.60e1.96 (m, 5H),
3.93 (s, 1H), 4.92 (s, 2H), 6.32 (d, J¼7.5 Hz, 1H), 7.29 (s, 5H), 8.08 (s,
1H), 10.20 (s, 1H) ppm; MS (EI) m/z 323 (Mþ). Anal. Calcd for
C18H21ON5: C, 66.85; H, 6.55; N, 21.66. Found: C, 66.42; H, 6.97; N,
21.54.
4.2.6. 9-Benzyl-6-(phenylamino)-7H-purin-8(9H)-one (8a). The gen-
eral procedure B was followed for the synthesis and purification giv-
ing a light yellow solid in 90% isolated yield. Mp 297e299 ꢀC; IR (KBr):
3415, 3363,1699,1646,1622,1594,1500,1467,1437, 747, 697 cmꢂ1; 1H
4.2.13. 6-(4-Chlorophenylamino)-9-(furan-2-yl-methyl)-7H-purin-8
(9H)-one (8h). The general procedure B was followed for the syn-
thesis and purification giving a pink solid in 44% isolated yield. Mp
314e316 ꢀC; IR (KBr): 3417, 3339, 1698, 1649,1622,1591,1493,1460,
NMR (300 MHz, DMSO-d6):
d
4.99 (s, 2H), 7.02 (t, J¼7.2 Hz, 1H),
7.28e7.37 (m, 7H), 7.68 (d, J¼7.8 Hz, 2H), 8.26(s,1H), 8.70 (s,1H),10.41
(s,1H) ppm; MS (EI) m/z 317 (Mþ). Anal. Calcd for C18H15ON5: C, 68.13;
H, 4.76; N, 22.07. Found: C, 68.26; H, 4.49; N, 21.70.
1413 cmꢂ1; 1H NMR (300 MHz, DMSO-d6):
d 4.98 (s, 2H), 6.36e6.40
(m, 2H), 7.38 (d, J¼9.0 Hz, 2H), 7.57 (s, 1H), 7.74 (d, J¼9.0 Hz, 2H),
8.29 (s, 1H), 9.05 (s, 1H), 10.56 (s, 1H) ppm; MS (EI) m/z 341 (Mþ).
Anal. Calcd for C16H12O2N5Cl: C, 56.23; H, 3.54; N, 20.49. Found: C,
56.20; H, 3.66; N, 20.16.
4.2.7. 9-Benzyl-6-(4-methoxyphenylamino)-7H-purin-8(9H)-one
(8b). The general procedure B was followed for the synthesis and
purification giving
283e284 ꢀC; IR (KBr): 3355, 1698, 1647, 1619, 1586, 1511, 1461, 1432,
1411, 1382, 822, 776, 696 cmꢂ1 1H NMR (300 MHz, DMSO-d6):
a white solid in 81% isolated yield. Mp
4.2.14. 6-(p-Toluidino)-9-(furan-2-ylmethyl)-7H-purin-8(9H)-one
(8i). The general procedure B was followed for the synthesis and
;
d
3.74 (s, 3H), 4.98 (s, 2H), 6.93 (d, J¼9.0 Hz, 2H), 7.25e7.36 (m, 5H),
purification giving
291e293 ꢀC; IR (KBr): 3415, 3352, 1703, 1649, 1624, 1605, 1585,
1513, 1461, 1416, 1384 cmꢂ1 1H NMR (300 MHz, DMSO-d6):
2.27
(s, 3H), 4.97 (s, 2H), 6.36e6.40 (m, 2H), 7.15 (d, J¼8.4 Hz, 2H), 7.56
(d, J¼8.4 Hz, 2H), 7.57 (s, 1H), 8.25 (s, 1H), 8.61 (s, 1H), 10.35 (s, 1H)
ppm; MS (EI) m/z 321 (Mþ). Anal. Calcd for C17H15O2N5: C, 63.54; H,
4.71; N, 21.79. Found: C, 63.46; H, 4.67; N, 21.50.
a white solid in 28% isolated yield. Mp
7.55 (d, J¼9.0 Hz, 2H), 8.20 (s, 1H), 8.58 (s, 1H), 10.32 (br s, 1H) ppm;
MS (EI) m/z 347 (Mþ). Anal. Calcd for C19H17O2N5: C, 65.69; H, 4.93;
N, 20.16. Found: C, 65.98; H, 4.74; N, 20.01.
;
d
4.2.8. 9-Benzyl-6-(3-chlorophenylamino)-7H-purin-8(9H)-one (8c).
The general procedure B was followed for the synthesis and purifi-
cation giving an off-white solid in 74% isolated yield. Mp 322e324 ꢀC;
IR (KBr): 3413, 3354, 1698, 1650, 1622, 1590, 1472, 1431, 1406, 768,
4.2.15. 6-(3-Chloro-4-fluorophenylamino)-9-(fu-ran-2-ylmethyl)-
7H-purin-8(9H)-one (8j). The general procedure B was followed for
the synthesis and purification giving a red solid in 38% isolated
yield. Mp 330e332 ꢀC; IR (KBr): 3414, 3353, 1702, 1647, 1625, 1598,
698 cmꢂ1 1H NMR (300 MHz, DMSO-d6):
; d 4.99 (s, 2H), 7.06 (d,
J¼6.9 Hz,1H), 7.32e7.45 (m, 7H), 8.00 (s,1H), 8.32 (s,1H), 8.92 (s,1H),
10.42 (s, 1H) ppm; MS (EI) m/z 351 (Mþ). Anal. Calcd for C18H14ON5Cl:
C, 61.46; H, 4.01; N, 19.91. Found: C, 61.62; H, 3.94; N, 19.66.
1495, 1466, 1424, 807, 780 cmꢂ1 1H NMR (300 MHz, DMSO-d6):
;
d
4.98 (s, 2H), 6.36e6.41 (m, 2H), 7.39e7.44 (m, 2H), 7.58 (s, 1H),
4.2.9. 9-Benzyl-6-(4-fluorophenylamino)-7H-purin-8(9H)-one (8d).
The general procedure B was followed for the synthesis and puri-
fication giving an off-white solid in 92% isolated yield. Mp
306e308 ꢀC; IR (KBr): 3360, 1697, 1647, 1621, 1597, 1510, 1465, 1432,
8.07 (dd, J¼2.4, 2.1 Hz, 1H), 8.31 (s, 1H), 8.91 (s, 1H), 10.36 (s, 1H)
ppm; MS (EI) m/z 359 (Mþ). Anal. Calcd for C16H11O2N5FCl: C, 53.42;
H, 3.08; N, 19.47. Found: C, 53.54; H, 3.53; N, 19.11.
1412, 829, 781, 696 cmꢂ1; 1H NMR (300 MHz, DMSO-d6):
d
4.98 (s,
4.2.16. 9-Phenethyl-6-(phenylamino)-7H-purin-8(9H)-one (8k). The
general procedure B was followed for the synthesis and purification
giving a white solid in 66% isolated yield. Mp 269e271 ꢀC; IR (KBr):
2H), 7.19 (t, J¼8.7 Hz, 2H), 7.25e7.32 (m, 5H), 7.65e7.66 (m, 2H),
8.25 (s, 1H), 8.74 (s, 1H), 10.37 (s, 1H) ppm; MS (EI) m/z 335 (Mþ).

Q.-F. Zhong, L.-P. Sun / Tetrahedron 66 (2010) 5107e5111
5111
3358, 3222, 1705, 1645, 1626, 1590, 1498, 1471, 1435, 1402, 751, 703,
696 cmꢂ1 1H NMR (300 MHz, DMSO-d6):
4.03 (t, J¼7.5 Hz, 2H), 7.02 (t, J¼7.2 Hz, 1H), 7.19e7.36 (m, 7H), 7.71
(d, J¼8.1 Hz, 2H), 8.26 (s, 1H), 8.81 (s, 1H), 10.22 (br s, 1H) ppm; MS
(EI) m/z 331 (Mþ). Anal. Calcd for C19H17ON5: C, 68.87; H, 5.17; N,
21.13. Found: C, 68.63; H, 5.03; N, 20.93.
References and notes
;
d
3.05 (t, J¼7.5 Hz, 2H),
1. (a) Laufer, S. A.; Domeyer, D. M.; Scior, T. R. F.; Albrecht, W.; Hauser, D. R. J.
J. Med. Chem. 2005, 48, 710e722; (b) Legraverend, M.; Grierson, D. S. Bioorg.
Med. Chem. 2006, 14, 3987e4006; (c) Hoffmann, M.; Chrzanowska, M.; Herm-
ann, T.; Rychlewski, J. J. Med. Chem. 2005, 48, 4482e4486; (d) Llauger, L.; He, H.;
Kim, J.; Aguirre, J.; Rosen, N.; Peters, U.; Davies, P.; Chiosis, G. J. Med. Chem. 2005,
48, 2892e2905; (e) Norman, T. C.; Gray, N. S.; Koh, J. T.; Schultz, P. G. J. Am.
Chem. Soc. 1996, 118, 7430e7431; (f) Chiosis, G.; Lu-cas, B.; Shtil, A.; Huezo, H.;
Rosen, N. Bioorg. Med. Chem. 2002, 10, 3555e3564; (g) Wright, L.; Barril, X.;
Dymock, B.; Sheridan, L.; Surgenor, A.; Beswick, M.; Drysdale, M.; Colli-er, A.;
Massey, A.; Davies, N.; Fink, A.; Fromont, C.; Aherne, W.; Boxall, K.; Sharp, S.;
Workman, P.; Hubbard, R. E. Chem. Biol. 2004, 11, 775e785; (h) Balzarini, J.;
Aquaro, S.; Hassan-Abdallah, A.; Daluge, S. M.; Perno, C.-F.; McGuigan, C. FEBS
Lett. 2004, 573, 38e44.
4.2.17. 6-(2-Methoxyphenylamino)-9-phenethyl-7H-purin-8(9H)-
one (8l). The general procedure B was followed for the synthesis
and purification giving a white solid in 80% isolated yield. Mp
270e272 ꢀC; IR (KBr): 3319, 3156, 1715, 1626, 1587, 1537, 1488, 1450,
1401, 752, 701 cmꢂ1 1H NMR (300 MHz, DMSO-d6):
; d 3.04 (t,
2. Beck, J. P.; Arvanitis, A. G.; Curry, M. A.; Rescinito, J. T.; Fitzgerald, L. W.; Gilligan,
P. J.; Zaczek, R.; Trainor, G. L. Bioorg. Med. Chem. Lett. 1999, 9, 967e972.
3. Reitz, A. B.; Goodman, M. G.; Pope, B. L.; Argentieri, D. C.; Bell, S. C.; Burr, L. E.;
Chourmouzis, E.; Come, J.; Goodman, J. H. J. Med. Chem. 1994, 37, 3561e3578.
4. (a) Kurimoto, A.; Ogino, T.; Ichii, S.; Isobe, Y.; Tobe, M.; Ogita, H.; Takaku, H.;
Sajiki, H.; Hirota, K.; Kawakami, H. Bioorg. Med. Chem. 2003, 11, 5501e5508; (b)
Hirota, K.; Kazaoka, K.; Sajiki, H. Bioorg. Med. Chem. 2003, 11, 2715e2722; (c)
Hirota, K.; Kazaoka, K.; Niimoto, I.; Sajiki, H. Org. Bioorg. Chem. 2003, 1,
1354e1365.
5. (a) Haesslein, J.-L.; Jullian, N. Curr. Top. Med. Chem. 2002, 2, 1037e1050; (b)
Moravec, J.; Krystof, V.; Hanus, J.; Havlícek, L.; Morav-cová, D.; Fuksová, K.;
Kuzma, M.; Lenobel, R.; Otyepka, M.; Strnad, M. Bioorg. Med. Chem. Lett. 2003,
13, 2993e2996.
J¼7.2 Hz, 2H), 3.87 (s, 3H), 4.01 (t, J¼7.2 Hz, 2H), 6.93e7.05 (m, 3H),
7.18e7.26 (m, 5H), 8.04 (s, 1H), 8.14 (d, J¼7.5 Hz, 1H), 8.21 (s, 1H),
10.96 (br s, 1H) ppm; MS (EI) m/z 361 (Mþ). Anal. Calcd for
C20H19O2N5$0.2H2O: C, 65.81; H, 5.36; N, 19.19. Found: C, 65.76; H,
5.00; N, 19.52.
4.2.18. 9-Cyclohexyl-6-(phenylamino)-7H-purin-8(9H)-one (8m).
The general procedure B was followed for the synthesis and puri-
fication giving a white solid in 74% isolated yield. Mp 236e238 ꢀC;
IR (KBr): 3400, 3333,1697,1645,1596,1497,1467, 743, 686 cmꢂ1; 1H
6. Hauser, D. R. J.; Scior, T.; Domeyer, D. M.; Kammerer, B.; Laufer, S. A. J. Med.
Chem. 2007, 50, 2060e2066.
NMR (300 MHz, DMSO-d6): d 1.18e1.42 (m, 3H), 1.66e1.85 (m, 5H),
2.22e2.36 (m, 2H), 4.17 (t, J¼12.0 Hz, 1H), 7.02 (t, J¼7.2 Hz, 1H), 7.34
(t, J¼7.8 Hz, 2H), 7.69 (d, J¼8.1 Hz, 2H), 8.26 (s, 1H), 8.68 (s, 1H),
10.36 (s, 1H) ppm; MS (EI) m/z 309 (Mþ). Anal. Calcd for C17H19ON5:
C, 66.00; H, 6.19; N, 22.64. Found: C, 65.68; H, 6.47; N, 22.50.
7. (a) Kutsuma, T.; Sakai, Y.; Ouchi, H.; Shiina, N.; Yamagishi, T.; Shibuya, S.;
Yokomatsu, T. Heterocycles 2005, 65, 1967e1973; (b) Isobe, Y.; Kurimoto, A.;
Tobe, M.; Hashimoto, K.; Nakamura, T.; Norimura, K.; Ogita, H.; Takaku, H. J.
Med. Chem. 2006, 49, 2088e2095.
8. (a) Hirota, K.; Kazaoka, K.; Niimoto, I.; Sajiki, H. Heterocycles 2001, 55,
2279e2282; (b) Kurimoto, A.; Ogino, T.; Ichii, S.; Isobe, Y.; Tobe, M.; Ogita, H.;
Takaku, H.; Sajiki, H.; Hirota, K.; Kawakami, H. Bioorg. Med. Chem. 2004, 12,
1091e1099.
9. Hirota, K.; Kazaoka, K.; Niimoto, I.; Kumihara, H.; Sajiki, H.; Isobe, Y.; Takaku, H.;
Tobe, M.; Ogita, H.; Ogino, T.; Ichii, S.; Kurimoto, A.; Kawakami, H. J. Med. Chem.
2002, 45, 5419e5422.
10. Weterings, J. J.; Khan, S.; van der Heden van Noort, G. J.; Melief, C. J. M.;
Overkleeft, H. S.; van der Burg, S. H.; Ossendorp, F.; van der Marel, G. A.;
Filippov, D. V. Bioorg. Med. Chem. Lett. 2009, 19, 2249e2251.
11. (a) Walters, I.; Austin, C.; Austin, R.; Bonnert, R.; Cage, P.; Christie, M.; Ebden,
M.; Gardiner, S.; Grahames, C.; Hill, S.; Hunt, F.; Jewell, R.; Lewis, S.; Martin, I.;
Nicholls, D.; Robinson, D. Bioorg. Med. Chem. Lett. 2008, 18, 798e803; (b) Shao,
Y.; Cole, A. G.; Brescia, M.-R.; Qin, L.-Y.; Duo, J.; Stauffer, T. M.; Rokosz, L. L.;
McGuinness, B. F.; Henderson, I. Bioorg. Med. Chem. Lett. 2009, 19, 1399e1402;
(c) Aguado, L.; Camarasa, M. a.-J.; Pérez-Pérez, M. a.-J. s J. Comb. Chem. 2009, 11,
210e212.
4.2.19. 6-(4-Chlorophenylamino)-9-cyclohexyl-7H-purin-8(9H)-one
(8n). The general procedure B was followed for the synthesis and
purification giving
282e284 ꢀC; IR (KBr): 3397, 1702, 1663, 1641, 1592, 1537, 1493,
1454, 823 cmꢂ1 1H NMR (300 MHz, DMSO-d6):
1.18e1.42 (m,
a white solid in 56% isolated yield. Mp
;
d
3H), 1.70e1.86 (m, 5H), 2.22e2.34 (m, 2H), 4.17 (t, J¼12.0 Hz, 1H),
7.38 (d, J¼9.0 Hz, 2H), 7.70 (d, J¼9.0 Hz, 2H), 8.27 (s, 1H), 8.78 (s,
1H), 10.30 (s, 1H) ppm; MS (EI) m/z 343 (Mþ). Anal. Calcd for
C17H18ON5Cl: C, 59.39; H, 5.28; N, 20.37. Found: C, 59.18; H, 5.64;
N, 20.66.
4.2.20. 9-Cyclohexyl-6-(2-methoxyphenylamino)-7H-purin-8(9H)-
one (8o). The general procedure B was followed for the synthesis
and purification giving a white solid in 41% isolated yield. Mp
244e246 ꢀC; IR (KBr): 3314, 3142, 1702, 1626, 1584, 1486, 1462,
12. Kuethe, J. T.; Wong, A.; Davies, I. W. J. Org. Chem. 2004, 69, 7752e7754.
13. (a) Kantam, M. L.; Yadav, J.; Laha, S.; Sreedhar, B.; Jha, S. Adv. Synth. Catal. 2007,
349, 1938e1942; (b) Zou, B.; Yuan, Q.; Ma, D. Angew. Chem., Int. Ed. 2007, 46,
2598e2601; (c) Chen, W.; Zhang, Y.; Zhu, L.; Lan, J.; Xie, R.; You, J. J. Am. Chem.
Soc. 2007, 129, 13879e13886; (d) Ma, H.-C.; Jiang, X.-Z. J. Org. Chem. 2007, 72,
8943e8946; (e) Maheswaran, H.; Krishna, G. G.; Prasanth, K. L.; Srinivas, V.;
Chaitanya, G. K.; Bhanuprakash, K. Tetrahedron 2008, 64, 2471e2479; (f) Ma, D.;
Cai, Q. Acc. Chem. Res. 2008, 41, 1450e1460; (g) Wang, D.; Ding, K. Chem.
Commun. 2009, 1891e1893; (h) Xu, H.; Wolf, C. Chem. Commun. 2009,
1715e1717; (i) Haldón, E.; Álvarez, E.; Nicasio, M. C.; Pérez, P. J. Organometallics
2009, 28, 3815e3821; (j) Liang, L.; Li, Z.; Zhou, X. Org. Lett. 2009, 11, 3294e3297.
14. (a) Zou, B.; Yuan, Q.; Ma, D. Org. Lett. 2007, 9, 4291e4294; (b) Barbero, N.; Carril,
M.; SanMartin, R.; Domínguez, E. Tetrahedron 2008, 64, 7283e7288; (c) Li, Z.;
Sun, H.; Jiang, H.; Liu, H. Org. Lett. 2008, 10, 3263e3266; (d) Diao, X.; Wang, Y.;
Jiang, Y.; Ma, D. J. Org. Chem. 2009, 74, 7974e7977.
746 cmꢂ1 1H NMR (300 MHz, DMSO-d6):
; d 1.18e1.42 (m, 3H),
1.69e1.86 (m, 5H), 2.23e2.34 (m, 2H), 3.88 (s, 3H), 4.17 (t, J¼11.4 Hz,
1H), 6.92e7.08 (m, 3H), 8.01 (s,1H), 8.14 (d, J¼7.8 Hz,1H), 8.21 (s,1H),
10.98 (s,1H) ppm; MS (EI) m/z 339 (Mþ). Anal. Calcd for C18H21O2N5:
C, 63.70; H, 6.24; N, 20.64. Found: C, 63.68; H, 6.68; N, 20.42.
Acknowledgements
15. Xu, D.; Xu, X.; Liu, Z.; Sun, L.-P.; You, Q. Synlett 2009, 7, 1172e1174.
16. (a) Lendrem, D.; Owen, M.; Godbert, S. Org. Process Res. Dev. 2001, 5, 324e327;
(b) Provencal, D. P.; Gesen-berg, K. D.; Wang, H.; Escobar, C.; Wong, H.; Brown,
M. A.; Staab, A. J.; Pendri, Y. R. Org. Process Res. Dev. 2004, 8, 903e908; (c) Walji,
D. V. B.; Storey, J. M. D.; Harrison, W. T. A. Acta Crystallogr. 2004, E60,
o1110eo1112.
This work was supported by the National Natural Science
Foundation of China (Project No. 20872181). The authors gratefully
thank Dan Xu for helpful discussions.
17. Baindur, N.; Chadha, N.; Player, M. R. J. Comb. Chem. 2003, 5, 653e659.
18. Gerhard, S.; Felix, P.U.S. Patent 5,294,710, 1993.
19. (a) Yuan, X.; Xu, X.; Zhou, X.; Yuan, J.; Mai, L.; Li, Y. J. Org. Chem. 2007, 72,
1510e1513; (b) Feng, Y.; Wang, H.; Sun, F.; Li, Y.; Fu, X.; Jin, K. Tetrahedron 2009,
65, 9737e9741.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2010.04.106.
20. Gaulon, C.; Dijkstra, H. P.; Springer, C. J. Synthesis 2005, 13, 2227e2233.