One-pot synthesis of 7,9-dialkylpurin-8-one analogues: Broad substrate scope

Article abstract of DOI:10.1021/jo402248d

The one-pot and direct synthesis of 7,9-dialkylpurin-8-one analogues with broad substrate scope has been developed. This copper-catalyzed C-H oxidation reaction could avoid multistep synthesis of quaternary ammonium salts and expand the scope of halogenated alkanes. Moreover, benzimidazole derivatives are also applicable in the catalytic system.

Full text of DOI:10.1021/jo402248d

Article
pubs.acs.org/joc
One-Pot Synthesis of 7,9-Dialkylpurin-8-one Analogues: Broad
Substrate Scope
Jian-Ping Li,† Yu Huang,† Ming-Sheng Xie,† Gui-Rong Qu,† Hong-Ying Niu,*,‡ Hai-Xia Wang,†
Bo-Wen Qin,† and Hai-Ming Guo*,†
†School of Chemistry and Chemical Engineering, Key Laboratory of Green Chemical Media and Reactions of Ministry of Education,
Henan Normal University, Xinxiang 453007, Henan, China
‡School of Chemistry and Chemical Engineering, Henan Institute of Science and Technology, Xinxiang 453003, China
S
* Supporting Information
ABSTRACT: The one-pot and direct synthesis of 7,9-dialkylpurin-8-one analogues with broad substrate scope has been
developed. This copper-catalyzed C−H oxidation reaction could avoid multistep synthesis of quaternary ammonium salts and
expand the scope of halogenated alkanes. Moreover, benzimidazole derivatives are also applicable in the catalytic system.
INTRODUCTION
RESULTS AND DISCUSSION
■
■
Initially, we started the study with the optimization of the
reaction conditions by using 9-benzyl-6-methoxy-9H-purine
(1a) and benzyl chloride (2a) as substrates. Due to the low cost
and ready availability, several copper sources were chosen as
catalysts, and the results showed that CuI was the best one for
the reaction, with 49% yield obtained (Table 1, entries 1−3).
Encouraged by the result, we screened some oxidants for the
reaction, and di-tert-butyl peroxide (DTBP) gave a better yield
(68% yield) than any other oxidant, such as N-chloro-
succinimide (NCS), K2S2O8, N-bromosuccinimide (NBS), or
PhI(OAc)2 (entries 3−7). Next, we also examined the effect of
various solvents including dimethylacetamide (DMAC), N-
methyl-2-pyrrolidone (NMP), CH3CN, cyclohexane, and
dioxane. The yield of the product was not satisfactory when
the reaction was conducted in a single solvent (entries 8−12).
Considering that most of the reagents and substrate used in the
reaction were not soluble in n-hexane, a mixed solvent was
attempted. To our delight, a high yield (87% yield) was
observed when a 15:1 mixture of n-hexane and DMAC was
used as solvent (entry 14). Both pivalic acid (t-BuCO2H) and
imidazole were essential for the reaction because the yield was
poor without either of them (entries 16 and 17). No product
was detected in the absence of the catalyst (entry 18).
Therefore, the optimal reaction conditions were CuI (20 mol
Purin-8-one analogues are key components in many natural
products, advanced intermediates, and biologically active
compounds (Figure 1),1 and they are commonly used as
potential anxiolytics and/or antidepressants (e.g., A),1a potent
interferon inducers (e.g., B and C),1b,c small-molecule
immunostimulants,2 and physiological antioxidants.3 Due to
their unique properties, the synthesis of such compounds has
been of increasing interest.4,5
A photoinduced oxidation reaction of quaternary ammonium
salts to afford purin-8-one derivatives has been developed.6a
However, the application of this method is limited to iodine
salts (Scheme 1, route a).6b Alternatively, H2O2 was employed
as an oxidant for the C−H oxidation reaction of the same
iodine salts as substrates (Scheme 1, route b).6a,c These
methods suffered from narrow substrate scope and multiple
steps because quaternary ammonium salts of N-aromatic
heterocyclic derivatives needed to be synthesized beforehand.
Considering the biological importance of purin-8-one deriva-
tives, a more efficient and direct method with broad substrate
scope for the synthesis of purin-8-one analogues is highly
desirable. In the context of ongoing projects for the synthesis of
purine analogues,7 we report here a copper-catalyzed one-pot
synthesis of 7,9-dialkylpurin-8-one analogues via a direct sp2
C−H oxidation reaction.8
Received: October 9, 2013
Published: November 15, 2013
© 2013 American Chemical Society
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Figure 1. Selected examples of purin-8-one analogues with biological activities.
high yields (3b−3g, 81−95%). When the substitutions of
purine at N9 were cycloalkyl, allyl, ester, or phenyl, the
reactions could proceed smoothly and provide high yields (3h−
3k, 84−91%). Purine derivatives with different substitutes at C6
including chlorine, oxygen, sulfur, and nitrogen could also
afford the expected purin-8-one products in satisfactory yields
(3l−3o, 70−82%).
Scheme 1. Strategies for the Synthesis of Purin-8-one
Derivatives from N7 Quaternary Ammonium Salts
The reaction of a variety of halogenated alkanes (including
Cl, Br, and I) was further explored under the optimized
conditions (Scheme 3). We were pleased to find that the
reaction with various halogenated alkanes all proceeded
smoothly and gave good to high yields (Scheme 3, 3p−3x,
71−87%). Longer length of the alkyl chain led to a little
decrease of the yield, which might be caused by the reduced
activity of the halogenated alkanes with the growth of the
carbon chain (3p−3t). Particularly, double bond, bromo, and
ester moieties were all well tolerated in this direct C−H
oxidation reaction (3v−3x), making further elaborations of the
corresponding 7,9-dialkylpurin-8-one analogues possible. Thus,
this strategy indeed expanded the scope of halogenated alkanes.
%) as catalyst, 2.0 equiv of DTBP as oxidant, 1.0 equiv of
imidazole and 1.2 equiv of t-BuCO2H as additives in a mixed
solvent (n-hexane/DMAC = 15:1, v/v) at 120 °C for 24 h.
To examine the generality of the reaction, a number of
purine derivatives were explored as substrates under the
improved reaction conditions, and the results are shown in
Scheme 2. The reaction of a series of 6-phenoxy-9-alkyl-
substituted purine derivatives with benzyl chloride proceeded
efficiently, and the corresponding products were obtained in
a
Table 1. Optimization of the Reaction Conditions
b
entry
catalyst
oxidant
NCS
solvent
additive
yield (%)
1
2
CuCl
CuBr
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
n-hexane
n-hexane
n-hexane
n-hexane
n-hexane
n-hexane
n-hexane
DMAC
imidazole, t-BuCO2H
imidazole, t-BuCO2H
imidazole, t-BuCO2H
imidazole, t-BuCO2H
imidazole, t-BuCO2H
imidazole, t-BuCO2H
imidazole, t-BuCO2H
imidazole, t-BuCO2H
imidazole, t-BuCO2H
imidazole, t-BuCO2H
imidazole, t-BuCO2H
imidazole, t-BuCO2H
imidazole, t-BuCO2H
imidazole, t-BuCO2H
imidazole, t-BuCO2H
imidazole
25
10
49
36
68
31
23
62
46
13
51
26
76
87
72
43
trace
NCS
3
NCS
4
K2S2O8
DTBP
NBS
5
6
7
PhI(OAc)2
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
8
9
NMP
10
11
12
13
14
15
16
17
18
CH3CN
cyclohexane
dioxane
n-hexane/DMAC (10/1)
n-hexane/DMAC (15/1)
n-hexane/DMAC (20/1)
n-hexane/DMAC (15/1)
n-hexane/DMAC (15/1)
n-hexane/DMAC (15/1)
t-BuCO2H
c
imidazole, t-BuCO2H
NR
a
Unless otherwise stated, all of the reactions were carried out with 1a (0.2 mmol), 2a (0.5 mmol), catalyst (20 mol %), oxidant (2.0 equiv), additive
b
c
(1.0 equiv of imidazole, 1.2 equiv of t-BuCO2H), solvent (1.0 mL), 120 °C, 24 h. Isolated yield. No reaction.
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a b
,
Scheme 2. Reaction of Various Purine Derivatives with Benzyl Chloride
a
Unless otherwise noted, all reactions were carried out with 1 (0.2 mmol), 2a (0.5 mmol), CuI (20 mol %), DTBP (2.0 equiv), imidazole (1.0
b
equiv), t-BuCO2H (1.2 equiv), n-hexane/DMAC (v/v = 15/1, 1.0 mL), 120 °C, 24 h. Isolated yield.
Encouraged by the above results, we used 1-benzyl-1H-
benzo[d]imidazole9 instead of purines as starting material to
react with various halogenated alkanes under the standard
reaction conditions, and the results are listed in Scheme 4.
Different alkyl chains of halogenated alkanes could afford the
desired product with good yields (5b−5f). More importantly,
some functional groups, including double bond, bromo, and
ester moieties, were also tolerated in this catalytic system, and
satisfactory yields of the products were obtained (5g−5j).
To further understand the structure of the product, we tried
to grow crystals of the products suitable for X-ray diffraction
analysis. The crystal of compound 5a confirmed that the
oxidation reaction occurred on the C2 position, and the
alkylation reaction occurred on the N3 position of 1-benzyl-1H-
benzo[d]imidazole (Figure 2), so the product was established
as 1,3-dibenzyl-1H-benzo[d]imidazol-2(3H)-one (5a).10
As for the reaction pathway, we speculated that the targeted
product might be produced by direct C−H oxidation from a
quaternary ammonium salt of purine analogues, which was first
generated from the substrates. To probe the nature of reaction,
in the absence of the catalyst, oxidant, and additives, we
performed the reaction of 4 and 2a in the solvent at 120 °C for
24 h, and intermediate 6a was obtained in a 51% isolated yield
(Scheme 5, A1), consistent with our speculation. When
compound 4 was reacted under the standard conditions in
the absence of BnCl, no reaction occurred (Scheme 5, B1). In
the second step, intermediate 6a was used as starting material
under the standard conditions, and the target product 5a was
obtained in 89% yield (Scheme 5, C1). To further verify the
reaction pathway, this one-pot reaction was monitored by TLC
and we found the presence of intermediate 6a (Scheme 5, D1).
Therefore, the reaction involved the formation of a quaternary
ammomium salt which gave the targeted product by direct C−
H oxidation under the standard reaction conditions. A detailed
mechanism investigation about how the C−H oxidation
reaction occurs is underway.
In conclusion, we have developed an efficient and direct
method for the synthesis of the 7,9-dialkylpurin-8-one
analogues via copper-catalyzed direct sp2 C−H oxidation.
This strategy could avoid multiple steps for the synthesis of
quaternary ammonium salts and expand the scope of
halogenated alkanes. A series of substrates involving purine
derivatives, benzimidazole derivatives, and halogenated alkanes
are applicable in this protocol at a 0.2 mmol scale. The
relatively inexpensive catalyst and the generally high yields
make this method very promising for the synthesis of many
biologically important C8 oxidated purines/imidazoles. The
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a b
,
Scheme 3. Reaction of 9-Benzyl-6-methoxy-9H-purine with Various Halogenated Alkanes
a
All reactions were carried out with 1a (0.2 mmol), 2 (0.5 mmol), CuI (20 mol %), DTBP (2.0 equiv), imidazole (1.0 equiv), t-BuCO2H (1.2
b
equiv), n-hexane/DMAC (v/v = 15/1, 1.0 mL), 120 °C, 24 h. Isolated yield.
mixture was cooled to room temperature, filtered through a plug of
Celite, and the Celite was rinsed with copious amounts ethyl acetate.
The solvent of the filtrate was removed under reduced pressure. The
residue was purified on a silica gel column (eluting with petroleum
ether/ethyl acetate), affording the corresponding product.
further expansion of the reaction and further investigation of
the reaction mechanism are in progress in our laboratory.
EXPERIMENTAL SECTION
■
General. Melting points were recorded with a micro melting point
apparatus and uncorrected. NMR spectra were recorded with a 400
NMR spectrometer for 1H NMR and 100 MHz for 13C NMR.
Chemical shifts δ were given in parts per million relative to
7,9-Dibenzyl-6-methoxy-7H-purin-8(9H)-one (3a): White
1
solid, 60.2 mg, 87% yield; mp 80−82 °C; H NMR (CDCl3, 400
MHz) δ 8.33 (s, 1H), 7.50−7.48 (m, 2H), 7.42−7.39 (m, 2H), 7.33−
7.25 (m, 6H), 5.17 (s, 2H), 5.13 (s, 2H), 4.06 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δ 152.9, 152.4, 150.4, 149.1, 137.2, 136.1, 128.7,
128.6, 128.4, 128.1, 127.9, 127.8, 107.5, 53.9, 46.3, 44.1; HRMS calcd
for C20H19N4O2 [M + H+] 347.1508, found 347.1503.
1
tetramethylsilane in CDCl3 for H and 13C NMR. High-resolution
mass spectra are taken using Q-TOF system, with electrospray
ionization (ESI) as the ionization method used for the HRMS
measurement. For column chromatography, 200−300 mesh silica gel
(GF254) was used as the stationary phase. All reactions were
monitored by thin layer chromatography (TLC). All reactions were set
up in air (with no use of a glovebox) and carried out in a sealed
pressure tube. All reagents (including CuI) and solvents were
purchased from commercial sources and used as received.
Typical Procedure. A dried pressure tube containing a stirbar was
charged with N-aromatic heterocycles (0.2 mmol), CuI (8.0 mg, 20
mol %), imidazole (14.0 mg, 1.0 equiv), and t-BuCOOH (25.0 mg, 1.2
equiv). Then halogenated alkanes (2.5 equiv), di-tert-butylperoxide
(DTBP, 0.075 mL, 2.0 equiv) and a mixed solvent of n-hexane and
DMAC (v/v = 15/1, 1.0 mL), were successively added to the pressure
tube. Then the pressure tube was fitted with a threaded sealing cap,
and the reaction mixture was stirred in an oil bath at 120 °C for 24 h.
After the completion of the reaction monitored by TLC, the resulting
7,9-Dibenzyl-6-phenoxy-7H-purin-8(9H)-one (3b): White
1
solid, 73.5 mg, 90% yield; mp 120−123 °C; H NMR (CDCl3, 400
MHz) δ 8.30 (s, 1H), 7.56−7.54 (m, 2H), 7.46−7.42 (m, 4H), 7.38−
7.27 (m, 7H), 7.07−7.05 (m, 2H), 5.30 (s, 2H), 5.20 (s, 2H); 13C
NMR (CDCl3, 100 MHz) δ 153.1, 152.1, 151.2, 150.6, 150.3, 137.1,
136.0, 129.8, 128.8, 128.6, 128.2, 128.1, 125.9, 121.6, 108.2, 46.5, 44.4;
HRMS calcd for C25H20N4NaO2 [M + Na+] 431.1473, found
431.1478.
7-Benzyl-9-(2-chlorobenzyl)-6-phenoxy-7H-purin-8(9H)-one
1
(3c): White solid, 72.6 mg, 82% yield; mp 116−118 °C; H NMR
(CDCl3, 400 MHz) δ 8.25 (s, 1H), 7.47−7.40 (m, 5H), 7.36−7.28 (m,
4H), 7.24−7.18 (m, 2H), 7.12−7.06 (m, 3H), 5.33 (d, J = 1.2 Hz,
4H); 13C NMR (CDCl3, 100 MHz) δ 153.1, 152.0, 151.3, 150.7,
150.4, 137.0, 133.0, 129.8, 129.1, 128.8, 128.3, 128.2, 128.1, 127.0,
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a b
,
Scheme 4. Reaction of 1-Benzyl-1H-benzo[d]imidazole with Various Halogenated Alkanes
a
All reactions were carried out with 4 (0.2 mmol), 2 (0.5 mmol), CuI (20 mol %), DTBP (2.0 equiv), imidazole (1.0 equiv), t-BuCO2H (1.2 equiv),
b
n-hexane/DMAC (v/v = 15/1, 1.0 mL), 120 °C, 24 h. Isolated yield.
13.9; HRMS calcd for C20H18N4NaO2 [M + Na+] 369.1326, found
369.1322.
7-Benzyl-2-chloro-9-isopropyl-6-phenoxy-7H-purin-8(9H)-
one (3f): White solid, 66.4 mg, 84% yield; mp 137−139 °C; 1H NMR
(CDCl3, 400 MHz) δ 7.43−7.39 (m, 4H), 7.34−7.25 (m, 4H), 7.04
(d, J = 7.6 Hz, 2H), 5.24 (s, 2H), 4.86−4.79 (m, 1H), 1.61 (d, J = 7.2
Hz, 6H); 13C NMR (CDCl3, 100 MHz) δ 152.5, 151.8, 151.6, 151.0,
150.3, 136.9, 129.7, 128.8, 128.1, 125.8, 121.2, 106.9, 46.3, 20.2;
HRMS calcd for C21H19ClN4NaO2 [M + Na+] 417.1097, found
417.1089.
Figure 2. X-ray structure of 5a.
7-Benzyl-9-(sec-butyl)-6-phenoxy-7H-purin-8(9H)-one (3g):
1
Colorless oil, 60.7 mg, 81% yield; H NMR (CDCl3, 400 MHz) δ
8.26 (s, 1H), 7.44−7.41 (m, 4H), 7.32−7.28 (m, 4H), 7.05 (d, J = 7.6
125.9, 121.6, 108.2, 46.6, 42.0; HRMS calcd for C25H19ClN4NaO2 [M
+ Na+] 465.1096, found 465.1089.
Hz, 2H), 5.30 (s, 2H), 4.62−4.57 (m, 1H), 2.30−2.21 (m, 1H), 1.98−
1.90 (m, 1H), 1.62 (d, J = 6.4 Hz, 3H), 0.91 (t, J = 7.0 Hz, 3H); 13C
NMR (CDCl3, 100 MHz) δ 153.0, 152.1, 151.1, 150.6, 150.1, 137.3,
129.7, 128.7, 128.0, 127.9, 125.7, 121.5, 108.0, 52.0, 46.3, 27.0, 18.4,
11.3; HRMS calcd for C22H22N4NaO2 [M + Na+] 397.1636, found
397.1635.
7-Benzyl-9-methyl-6-phenoxy-7H-purin-8(9H)-one (3d):
White solid, 63.1 mg, 95% yield; mp 117−118 °C; 1H NMR
(CDCl3, 400 MHz) δ 8.27 (s, 1H), 7.45−7.41 (m, 4H), 7.33−7.28 (m,
4H), 7.07−7.05 (m, 2H), 5.28 (s, 2H), 3.53 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δ 153.4, 152.1, 151.0, 150.7, 150.4, 137.0, 129.8,
128.7, 128.2, 128.0, 125.8, 121.5, 108.2, 46.4, 26.8; HRMS calcd for
C19H17N4O2 [M + H+] 333.1339, found 333.1346.
7-Benzyl-9-cyclopentyl-6-phenoxy-7H-purin-8(9H)-one (3h):
Yellow oil, 65.7 mg, 85% yield; 1H NMR (CDCl3, 400 MHz) δ 8.25 (s,
1H), 7.46−7.40 (m, 4H), 7.34−7.27 (m, 4H), 7.07−7.05 (m, 2H),
5.28 (s, 2H), 4.98−4.89 (m, 1H), 2.36−2.28 (m, 2H), 2.08−1.99 (m,
4H), 1.75−1.65 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 152.9,
152.2, 151.1, 150.5, 150.0, 137.2, 129.7, 128.7, 128.2, 127.9, 125.7,
121.5, 108.2, 54.0, 46.3, 29.5, 24.8; HRMS calcd for C23H23N4O2 [M +
H+] 387.1814, found 387.1816.
7-Benzyl-9-ethyl-6-phenoxy-7H-purin-8(9H)-one (3e): White
1
solid, 64.4 mg, 93% yield; mp 101−103 °C; H NMR (CDCl3, 400
MHz) δ 8.28 (s, 1H), 7.45−7.41 (m, 4H), 7.34−7.28 (m, 4H), 7.07
(d, J = 8.0 Hz, 2H), 5.30 (s, 2H), 4.10 (q, J = 7.2 Hz, 2H), 1.44 (t, J =
7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 153.0, 152.2, 151.0,
150.4, 137.2, 129.8, 128.7, 128.1, 128.0, 125.8, 121.5, 108.2, 46.3, 36.0,
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Scheme 5. Possible Reaction Pathway
9-Allyl-7-benzyl-6-phenoxy-7H-purin-8(9H)-one (3i): White
solid, 62.4 mg, 87% yield; mp 97−99 °C; H NMR (CDCl3, 400
5.34 (s, 2H), 5.13 (s, 2H), 3.25 (t, J = 7.2 Hz, 2H), 1.73−1.63 (m,
2H), 0.97 (t, J = 7.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 153.1,
150.8, 146.9, 145.8, 136.9, 135.9, 128.7, 128.5, 128.0, 127.8, 127.4,
119.4, 46.1, 44.0, 31.7, 22.9, 13.4; HRMS calcd for C22H22N4NaOS [M
+ Na+] 413.1399, found 413.1407.
6-(1H-Benzo[d][1,2,3]triazol-1-yl)-7,9-dibenzyl-7H-purin-
8(9H)-one (3o): White solid, 67.6 mg, 78% yield; mp 163−165 °C;
1H NMR (CDCl3, 400 MHz) δ 8.69 (s, 1H), 8.10 (d, J = 7.2 Hz, 1H),
1
MHz) δ 8.26 (s, 1H), 7.44−7.41 (m, 4H), 7.31−7.28 (m, 4H), 7.05
(d, J = 8.0 Hz, 2H), 6.06−6.00 (m, 1H), 5.29−5.25 (m, 4H), 4.63 (d, J
= 5.6 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 152.9, 152.1, 151.2,
150.5, 150.3, 137.1, 131.2, 129.8, 128.7, 128.1, 128.0, 125.8, 121.5,
118.2, 108.2, 46.4, 42.8; HRMS calcd for C21H18N4NaO2 [M + Na+]
381.1327, found 381.1322.
7.63−7.58 (m, 3H), 7.48−7.33 (m, 5H), 6.81−6.73 (m, 3H), 6.46 (d, J
= 7.2 Hz, 2H), 5.40 (s, 2H), 5.32 (s, 2H); 13C NMR (CDCl3, 100
MHz) δ 153.6, 152.7, 150.6, 146.0, 135.6, 135.4, 135.0, 132.4, 129.0,
128.9, 128.6, 128.4, 128.1, 127.3, 125.9, 125.2, 119.8, 114.9, 111.9,
46.0, 44.7; HRMS calcd for C25H20N7O [M + H+] 434.1716, found
434.1724.
9-Benzyl-6-methoxy-7-methyl-7H-purin-8(9H)-one (3p):
White crystals, 44.3 mg, 82% yield; mp 111−113 °C; 1H NMR
(CDCl3, 400 MHz) δ 8.32 (s, 1H), 7.48−7.46 (m, 2H), 7.32−7.23 (m,
3H), 5.10 (s, 2H), 4.06 (s, 3H), 3.57 (s, 3H); 13C NMR (CDCl3, 100
MHz) δ 152.9, 152.6, 150.1, 148.8, 136.2, 128.6, 128.5, 127.9, 108.1,
53.9, 44.0, 29.4; HRMS calcd for C14H15N4O2 [M + H+] 271.1198,
found 271.1190.
Ethyl 2-(7-benzyl-8-oxo-6-phenoxy-7H-purin-9(8H)-yl)-
1
acetate (3j): White solid, 67.9 mg, 84% yield; mp 89−91 °C; H
NMR (CDCl3, 400 MHz) δ 8.25 (s, 1H), 7.42−7.41 (m, 4H), 7.34−
7.28 (m, 4H), 7.04 (d, J = 8.0 Hz, 2H), 5.31 (s, 2H), 4.77 (s, 2H), 4.27
(q, J = 7.2 Hz, 2H), 1.31 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl3, 100
MHz) δ 167.1, 152.9, 152.0, 151.3, 150.6, 150.2, 136.9, 129.8, 128.7,
128.0, 125.9, 121.5, 108.4, 62.1, 46.5, 41.4, 14.2; HRMS calcd for
C22H21N4O4 [M + H+] 405.1548, found 405.1557.
7-Benzyl-2-chloro-6-phenoxy-9-phenyl-7H-purin-8(9H)-one
1
(3k): White solid, 78.1 mg, 91% yield; mp 231−233 °C; H NMR
(CDCl3, 400 MHz) δ 7.68−7.66 (m, 2H), 7.56−7.42 (m, 7H), 7.36−
7.28 (m, 4H), 7.09−7.07 (m, 2H) 5.33 (s, 2H); 13C NMR (CDCl3,
100 MHz) δ 152.2, 151.7, 151.6, 151.2, 151.0, 136.6, 132.3, 129.8,
129.3, 128.8, 128.4, 128.3, 128.2, 126.0, 125.7, 121.2, 107.1, 46.7;
HRMS calcd for C24H17ClN4NaO2 [M + Na+] 451.0926, found
451.0932.
9-Benzyl-7-ethyl-6-methoxy-7H-purin-8(9H)-one (3q): White
1
solid, 45.5 mg, 80% yield; mp 95−97 °C; H NMR (CDCl3, 400
MHz) δ 8.32 (s, 1H), 7.48−7.46 (m, 2H), 7.32−7.23 (m, 3H), 5.10 (s,
2H), 4.07 (s, 3H), 4.03 (t, J = 7.2 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H);
13C NMR (CDCl3, 100 MHz) δ 152.5, 152.3, 150.1, 149.0, 136.2,
128.6, 128.4, 127.8, 107.4, 53.9, 44.0, 37.9, 15.3; HRMS calcd for
C15H16N4NaO2 [M + Na+] 307.1173, found 307.1165.
7,9-Dibenzyl-6-chloro-7H-purin-8(9H)-one (3l): Colorless oil,
1
49.1 mg, 70% yield; H NMR (CDCl3, 400 MHz) δ 8.46 (s, 1H),
7.51−7.48 (m, 2H), 7.38−7.28 (m, 8H), 5.34 (s, 2H), 5.17 (s, 2H);
13C NMR (CDCl3, 100 MHz) δ 153.1, 150.8, 150.2, 136.3, 136.0,
135.3, 128.9, 128.7, 128.3, 128.1, 127.4, 119.3, 45.4, 44.5; HRMS calcd
for C19H15ClN4NaO [M + Na+] 373.0820, found 373.0827.
9-Benzyl-6-methoxy-7-propyl-7H-purin-8(9H)-one (3r):
1
White solid, 44.2 mg, 74% yield; mp 95−97 °C; H NMR (CDCl3,
7,9-Dibenzyl-2,6-dimethoxy-7H-purin-8(9H)-one (3m): Col-
400 MHz) δ 8.31 (s, 1H), 7.46−7.44 (m, 2H), 7.31−7.22 (m, 3H),
5.10 (s, 2H), 4.06 (s, 3H), 3.94 (t, J = 7.2 Hz, 2H), 1.80−1.70 (m,
2H), 0.92 (t, J = 7.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 152.8,
152.2, 150.1, 148.9, 136.2, 128.6, 128.4, 127.8, 107.7, 53.9, 44.4, 43.9,
23.2, 10.9; HRMS calcd for C16H18N4NaO2 [M + Na+] 321.1317,
found 321.1322.
1
orless oil, 56.8 mg, 82% yield; H NMR (CDCl3, 400 MHz) δ 7.49−
7.47 (m, 2H), 7.37−7.27 (m, 8H), 5.10 (s, 2H), 5.06 (s, 2H), 4.01 (s,
3H), 3.96 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 160.2, 153.7,
153.2, 150.8, 137.4, 136.3, 128.7, 128.6, 128.0, 127.9, 127.7, 102.2,
55.0, 53.9, 46.2, 44.1; HRMS calcd for C21H21N4O3 [M + H+]
377.1600, found 377.1608.
9-Benzyl-7-butyl-6-methoxy-7H-purin-8(9H)-one (3s): White
1
7,9-Dibenzyl-6-(propylthio)-7H-purin-8(9H)-one (3n): White
solid, 48.7 mg, 78% yield; mp 69−70 °C; H NMR (CDCl3, 400
1
solid, 56.3 mg, 72% yield; mp 79−81 °C; H NMR (CDCl3, 400
MHz) δ 8.32 (s, 1H), 7.47−7.45 (m, 2H), 7.32−7.23 (m, 3H), 5.10 (s,
2H), 4.06 (s, 3H), 3.98 (t, J = 7.2 Hz, 2H), 1.74−1.67 (m, 2H), 1.40−
MHz) δ 8.49 (s, 1H), 7.48 (d, J = 6.8 Hz, 2H), 7.35−7.28 (m, 8H),
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Article
1.31 (m, 2H), 0.94 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz)
δ 152.7, 152.2, 150.1, 148.9, 136.2, 128.6, 128.4, 127.8, 107.7, 53.9,
44.0, 42.6, 32.0, 19.7, 13.6; HRMS calcd for C17H20N4NaO2 [M +
Na+] 335.1478, found 335.1478.
127.6, 127.4, 121.2, 121.0, 108.3, 107.7, 44.8, 42.8, 21.8, 11.4; HRMS
calcd for C17H18N2NaO [M + Na+] 289.1319, found 289.1311.
1-Benzyl-3-butyl-1H-benzo[d]imidazol-2(3H)-one (5e): Light
yellow oil, 44.9 mg, 80% yield; 1H NMR (CDCl3, 400 MHz) δ 7.34−
7.24 (m, 5H), 7.09−6.98 (m, 3H), 6.88 (d, J = 7.2 Hz, 1H), 5.09 (s,
2H), 3.94 (t, J = 7.2 Hz, 2H), 1.82−1.75 (m, 2H), 1.43−1.39 (m, 2H),
0.99 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 154.4, 136.4,
129.5, 129.3, 128.7, 127.6, 127.5, 121.2, 121.0, 108.3, 107.7, 44.8, 41.0,
30.5, 20.1, 13.8; HRMS calcd for C18H20N2NaO [M + Na+] 303.1462,
found 303.1468.
9-Benzyl-6-methoxy-7-pentyl-7H-purin-8(9H)-one (3t): Light
1
yellow solid, 46.3 mg, 71% yield; mp 42−43 °C; H NMR (CDCl3,
400 MHz) δ 8.33 (s, 1H), 7.48−7.46 (m, 2H), 7.33−7.27 (m, 3H),
5.12 (s, 2H), 4.07 (s, 3H), 3.98 (t, J = 6.4 Hz, 2H), 1.73 (t, J = 6.2 Hz,
2H), 1.33 (s, 4H), 0.89 (d, J = 6.0 Hz, 3H); 13C NMR (CDCl3, 100
MHz) δ 152.7, 152.2, 150.1, 149.0, 136.2, 128.6, 128.4, 127.8, 107.7,
53.9, 43.9, 42.8, 29.6, 28.6, 22.2, 13.9; HRMS calcd for C18H22N4NaO2
[M + Na+] 349.1643, found 349.1635.
1-Benzyl-3-pentyl-1H-benzo[d]imidazol-2(3H)-one (5f): Col-
1
orless oil, 42.4 mg, 72% yield; H NMR (CDCl3, 400 MHz) δ 7.32−
7.23 (m, 5H), 7.08−6.97 (m, 3H), 6.87 (d, J = 7.2 Hz, 1H), 5.08 (s,
2H), 3.92 (t, J = 7.4 Hz, 2H), 1.82−1.75 (m, 2H), 1.39−1.35 (m, 4H),
0.90 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 154.4, 136.4,
129.5, 129.2, 128.7, 127.6, 127.4, 121.2, 121.0, 108.3, 107.7, 44.8, 41. 3,
29.0, 28.1, 22.4, 14.0; HRMS calcd for C19H22N2NaO [M + Na+]
317.1628, found 317.1624.
7-Allyl-9-benzyl-6-methoxy-7H-purin-8(9H)-one (3u): Light
yellow solid, 45.0 mg, 76% yield; mp 70−71 °C; H NMR (CDCl3,
1
400 MHz) δ 8.32 (s, 1H), 7.47−7.45 (m, 2H), 7.32−7.23 (m, 3H),
5.98−5.89 (m, 1H), 5.18−5.13 (m, 2H), 5.11 (s, 2H), 4.60−4.58 (m,
2H), 4.05 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 152.5, 152.4,
150.3, 149.0, 136.1, 132.7, 128.6, 128.4, 127.9, 117.6, 107.5, 53.9, 44.9,
44.0; HRMS calcd for C16H16N4NaO2 [M + Na+] 319.1173, found
319.1165.
1-Allyl-3-benzyl-1H-benzo[d]imidazol-2(3H)-one (5g): Dark
yellow oil, 44.9 mg, 85% yield; 1H NMR (CDCl3, 400 MHz) δ 7.36−
7.25 (m, 5H), 7.08−6.99 (m, 3H), 6.90 (d, J = 7.2 Hz, 1H), 6.00−5.90
(m, 1H), 5.27(s, 1H), 5.24 (d, J = 4.8 Hz, 1H), 5.10 (s, 2H), 4.57 (d, J
= 5.2 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 154.2, 136.4, 132.1,
129.4, 129.2, 128.7, 127.7, 127.5, 121.3, 117.6, 108.3, 44.9, 43.6;
HRMS calcd for C17H16N2NaO [M + Na+] 287.1162, found 287.1155.
1-Benzyl-3-(4-bromobutyl)-1H-benzo[d]imidazol-2(3H)-one
9-Benzyl-7-(4-bromobutyl)-6-methoxy-7H-purin-8(9H)-one
1
(3v): Light yellow oil, 56.3 mg, 72% yield; H NMR (CDCl3, 400
MHz) δ 8.33 (s, 1H), 7.45 (d, J = 6.8 Hz, 2H), 7.32−7.23 (m, 3H),
5.10 (s, 2H), 4.08 (s, 3H), 4.02 (t, J = 6.4 Hz, 2H), 3.44 (t, J = 5.8 Hz,
2H), 1.91−1.90 (m, 4H); 13C NMR (CDCl3, 100 MHz) δ 152.7,
152.3, 150.3, 149.0, 136.1, 128.6, 128.4, 127.9, 107.5, 54.0, 44.0, 41.8,
32.9, 29.5, 28.4; HRMS calcd for C17H19BrN4NaO2 [M + Na+]
413.0584, found 413.0584.
1
(5h): Yellow oil, 56.0 mg, 78% yield; H NMR (CDCl3, 400 MHz) δ
7.34 −7.24 (m, 5H), 7.10−6.99 (m, 3H), 6.89−6.87 (m, 1H), 5.08 (s,
2H), 3.98 (t, J = 6.6 Hz, 2H), 3.48 (t, J = 5.6 Hz, 2H), 1.97−1.95 (m,
4H); 13C NMR (CDCl3, 100 MHz) δ 154. 4, 136.3, 129.2, 128.8,
127.7, 127.4, 121.4, 121.3, 108.4, 107.6, 44.9, 40.2, 33.0, 29.7, 26.9;
HRMS calcd for C18H19BrN2NaO [M + Na+] 381.0579, found
381.0573.
9-Benzyl-7-(2-bromoethyl)-6-methoxy-7H-purin-8(9H)-one
1
(3w): White solid, 53.0 mg, 73% yield; mp 110−112 °C; H NMR
(CDCl3, 400 MHz) δ 8.36 (s, 1H), 7.47 (d, J = 7.6 Hz, 2H), 7.34−
7.29 (m, 3H), 5.13 (s, 2H), 4.39 (t, J = 7.0 Hz, 2H), 4.10 (s, 3H), 3.65
(t, J = 6.6 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 152.5, 152.3,
150.7, 149.1, 136. 0, 128.7, 128.4, 128.0, 107.3, 54.2, 44.1, 43.9, 29.2;
HRMS calcd for C15H15BrN4NaO2 [M + Na+] 385.0270, found
385.0271.
1-Benzyl-3-(4-nitrobenzyl)-1H-benzo[d]imidazol-2(3H)-one
1
(5i): Yellow solid, 59.7 mg, 83% yield;mp 159−161 °C; H NMR
(CDCl3, 400 MHz) δ 8.19 (d, J = 8.8 Hz, 2H), 7.49 (d, J = 8.8 Hz,
2H), 7.35−7.27 (m, 5H), 7.05−6.98 (m, 2H), 6.94−6.92 (m, 1H),
6.83−6.81 (m, 1H), 5.21 (s, 2H), 5.13 (s, 2H); 13C NMR (CDCl3,
100 MHz) δ 154.4, 147.6, 143.6, 136.0, 129.3, 128.8, 128.1, 127.8,
127.5, 124.1, 121.9, 121.6, 108.7, 107.9, 45.1, 44.3; HRMS calcd for
C21H17N3NaO3 [M + Na+] 382.1169, found 382.1162.
Ethyl 2-(9-benzyl-6-methoxy-8-oxo-8,9-dihydro-7H-purin-7-
1
yl)acetate (3x): White solid, 57.5 mg, 84% yield; mp 81−83 °C; H
NMR (CDCl3, 400 MHz) δ 8.34 (s, 1H), 7.45 (d, J = 7.2 Hz, 2H),
7.32−7.23 (m, 3H), 5.13 (s, 2H), 4.74 (s, 2H), 4.23 (q, J = 7.2 Hz,
2H), 4.02 (s, 3H), 1.26 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl3, 100
MHz) δ 167.9, 152.7, 152.5, 150. 7, 149.1, 135.9, 128.6, 128.2, 127.9,
107.6, 61.7, 54.0, 44.1, 43.8, 14.1; HRMS calcd for C17H18N4NaO4 [M
+ Na+] 365.1222, found 365.1220.
Ethyl-2-(3-benzyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-
1-yl)acetate (5j): White solid, 34.2 mg, 51% yield; mp 126−128 °C;
1H NMR (CDCl3, 400 MHz) δ 7.31−7.24 (m, 5H), 7.07−6.99 (m,
2H), 6.91−6.87 (m, 2H), 5.09 (s, 2H), 4.67 (s, 2H), 4.23 (q, J = 7.2
Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ
167.8, 154.3, 136.1, 129.3, 129.2, 128.7, 127.7, 127.4, 121.8, 121.6,
108.6, 107.7, 61.8, 44.9, 42.4, 14.1; HRMS calcd for C18H18N2NaO3
[M + Na+] 333.1218, found 333.1210.
1,3-Dibenzyl-1H-benzo[d]imidazol-2(3H)-one (5a): White
1
solid, 59.1 mg, 94% yield; mp 106−108 °C; H NMR (CDCl3, 400
MHz) δ 7.36−7.26 (m, 10H), 6.99−6.96 (m, 2H), 6.90−6.86 (m,
2H), 5.13 (s, 4H); 13C NMR (CDCl3, 100 MHz) δ 154.6, 136.4,
129.3, 128.8, 127.7, 127.5, 121.4, 108.4, 45.0; HRMS calcd for
C21H19N2O [M + H+] 315.1499, found 315.1492.
1,3-Dibenzyl-1H-benzo[d]imidazol-3-ium Chloride (6a):
1
White solid, mp 207−209 °C; H NMR (DMSO-d6, 400 MHz) δ
10.73 (s, 1H), 8.01−8.00 (m, 2H), 7.59−7.58 (m, 6H), 7.40−7.33 (m,
6H), 5.88 (s, 4H); 13C NMR (DMSO-d6, 100 MHz) δ 143.4, 134.6,
131.5, 129.5, 129.2, 128.8, 127.2, 114.5, 50.5.
1-Benzyl-3-methyl-1H-benzo[d]imidazol-2(3H)-one (5b):
1
White solid, 39.1 mg, 82% yield; mp 85−87 °C H NMR (CDCl3,
400 MHz) δ 7.35−7.23 (m, 5H), 7.10−6.97 (m, 3H), 6.88 (d, J = 7.6
Hz, 1H), 5.08 (s, 2H), 3.46 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ
154.6, 136.4, 130.1, 129.2, 128.7, 127.6, 127.5, 121.3, 121.2, 108.2,
107.4, 44.9, 27.2; HRMS calcd for C15H14N2NaO [M + Na+]
261.0992, found 261.0998.
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of 1H and 13C NMR spectra of compounds 3a−3x, 5a−
5j, and 6a. This material is available free of charge via the
Internet at http://pubs.acs.org.
1-Benzyl-3-ethyl-1H-benzo[d]imidazol-2(3H)-one (5c): Light
1
yellow solid, 40.9 mg, 81% yield; mp 81−83 °C; H NMR (CDCl3,
400 MHz) δ 7.33−7.24 (m, 5H), 7.09−6.98(m, 3H), 6.88 (d, J = 7.6
Hz, 1H), 5.09 (s, 2H), 4.00 (q, J = 7.2 Hz, 2H), 1.38 (t, J = 7.2 Hz,
3H); 13C NMR (CDCl3, 100 MHz) δ 154.1, 136.4, 129.3, 129.2,
128.7, 127.6, 127.5, 121.2, 121.0, 108.3, 107.5, 44.8, 36.0, 13.7; HRMS
calcd for C16H16N2NaO [M + Na+] 275.1158, found 275.1155.
1-Benzyl-3-propyl-1H-benzo[d]imidazol-2(3H)-one (5d): Yel-
low oil, 40.5 mg, 76% yield; 1H NMR (CDCl3, 400 MHz) δ 7.33−7.24
(m, 5H), 7.09−6.98 (m, 3H), 6.88 (d, J = 7.6 Hz, 1H), 5.09 (s, 2H),
3.91 (t, J = 7.2 Hz, 2H), 1.88−1.79 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H);
13C NMR (CDCl3, 100 MHz) δ 154.5, 136.5, 129.6, 129.2, 128.7,
AUTHOR INFORMATION
Corresponding Authors
*E-mail: niu_hy@163.com.
■
*E-mail: guohm518@hotmail.com. Fax: (+) (+86) 373-
3329276.
Notes
The authors declare no competing financial interest.
12635
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Article
2011, 47, 5608. (d) Guo, H.-M.; Jiang, L.-L.; Niu, H.-Y.; Rao, W.-H.;
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ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of China (Grant Nos. 21072047,
21172059, 21272059, 21202039, 21372066, and 21372064),
Excellent Youth Foundation of Henan Scientific Committee
(No. 114100510012), the Program for Innovative Research
Team from the University of Henan Province
(2012IRTSTHN006), the Program for Changjiang Scholars
and Innovative Research Team in the University (IRT1061),
the Program for Science&Technology Innovation Talents in
Universities of Henan Province (No. 13HASTIT013), and the
Foundation for University Young Key Teacher by Henan
Province of China (No. 2011GGJS-132).
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