A copper-catalyzed domino route toward purine-fused tricyclic derivatives

Article abstract of DOI:10.1021/jo4025489

Purine-fused tricyclic derivatives have been synthesized via a copper-catalyzed domino Michael/oxidative cross-coupling reaction between adenines and nitroolefins for the first time. With air as the oxidant, this method has high regioselectivity, which provides a new route for constructing purine-nucleoside-conjugated systems with two newly formed C-N bonds. Meanwhile, purine nucleosides with an exocyclic amino group could be obtained easily by simple reduction, which may lead to potential applications in fluorescence recognition of various bases in vivo.

Full text of DOI:10.1021/jo4025489

Article
pubs.acs.org/joc
A Copper-Catalyzed Domino Route toward Purine-Fused Tricyclic
Derivatives
Ming-Sheng Xie,† Zhi-Liang Chu,† Hong-Ying Niu,‡ Gui-Rong Qu,*,† and Hai-Ming Guo*,†
†Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical
Media and Reactions, Ministry of Education, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang,
Henan 453007, P. R. China
‡School of Chemistry and Chemical Engineering, Henan Institute of Science and Technology, Xinxiang, Henan 453003, P. R. China
S
* Supporting Information
ABSTRACT: Purine-fused tricyclic derivatives have been
synthesized via a copper-catalyzed domino Michael/oxidative
cross-coupling reaction between adenines and nitroolefins for
the first time. With air as the oxidant, this method has high
regioselectivity, which provides a new route for constructing
purine-nucleoside-conjugated systems with two newly formed
C−N bonds. Meanwhile, purine nucleosides with an exocyclic
amino group could be obtained easily by simple reduction, which may lead to potential applications in fluorescence recognition
of various bases in vivo.
with adenine or adenosine (Scheme 1a).5 Later, Singer’s group
developed the reaction of p-benzoquinone with deoxyadeno-
sine to afford purine-fused polycyclic derivatives with an
exocyclic hydroxyl group (Scheme 1b).4 However, the
limitation of previous methods is the lack of structural diversity
in the products. Very recently, our group reported the
INTRODUCTION
The valuable biological and medicinal activities of purine
■
analogues have made the modification of purines among the
hot topics in the chemical and pharmaceutical fields.1 In
particular, purine-fused tricyclic and polycyclic derivatives have
attracted considerable attention because of their unique
properties and special conjugated structures.2 For example,
purine-fused tricyclic 1,N6-ethenoadenine 3′,5′-monophosphate
(Figure 1) is a strongly fluorescent probe3 and 9-hydroxy-1,N6-
Scheme 1. Strategies for the Synthesis of Purine-Fused
Polycyclic Derivatives
Figure 1. Selected examples of purine-fused polycyclic derivatives
exhibiting strong fluorescence or biological activity.
benzetheno-2′-deoxyadenosine (Figure 1) exhibits binding
activity toward HeLa cells.4 It is well-known that the exocyclic
hydroxyl or amino group in the nucleoside derivatives has a
vital function in base pairing. If a hydroxyl or amino group is
introduced into purine-fused polycyclics, they may work as
fluorescent probes to recognize various bases in vivo. Thus,
searching for a useful and efficient approach for the synthesis of
purine-fused polycyclic derivatives with exocyclic hydroxyl or
amino groups is highly desirable.
The classical approach for the synthesis of purine-fused
polycyclic derivatives is via the reaction of haloacetaldehyde
Received: November 18, 2013
© XXXX American Chemical Society
A
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a
Table 1. Optimization of the Reaction Conditions
b
c
entry
catalyst
oxidant
solvent
additive
T (°C)
yield (%)
1
2
Cu(OAc)2
Cu(OAc)2
CuCl
CuBr
CuI
PhI(OAc)2
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DCE
−
−
−
−
−
−
−
−
120
120
120
120
120
120
120
120
120
120
120
120
70
41
46
50
61
43
62
<5
<5
0
O2
3
O2
4
O2
5
O2
6
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
air
7
30% H2O2
8
K2S2O8
air
9
Cs2CO3
HOAc
TFA
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
10
11
12
13
14
15
16
17
air
51
46
75
43
37
85
52
0
air
air
air
air
CH3CN
DMSO
xylene
EG
70
air
130
100
120
air
air
d
18
air
DMSO
70
trace
a
b
Reaction conditions: 1a (0.3 mmol), 2a (1.2 equiv), catalyst (10 mol %), additive (3.0 equiv), solvent (2.0 mL), 24 h. Oxidant (3.0 equiv); O2 or
c
d
air (1.0 atm). Isolated yields. Reaction time: 48 h.
a b
,
Scheme 2. Reaction with Various Adenines
a
b
Reaction conditions: 1 (0.3 mmol), 2a (1.2 equiv), CuBr (10 mol %), PivOH (3.0 equiv), DMSO (2.0 mL), 130 °C, 24 h. Isolated yields are
shown.
intramolecular C(sp2)−H amination reaction of 6-anilinopurine
nucleosides to construct purine-fused polycyclic derivatives, in
which the starting material should be preprepared beforehand
(Scheme 1c).6 Although great endeavors have been devoted to
the synthesis of purine-fused polycyclic derivatives, the
structural diversity of these derivatives is still very limited.
Thus, developing an efficient method to obtain structurally
diverse purine-fused polycyclic derivatives without preprepara-
B
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a
Table 2. Reaction with Various Nitroolefins
a
b
Reaction conditions: 1 (0.3 mmol), 2a (1.2 equiv), catalyst (10 mol %), PivOH (3.0 equiv), DMSO (2.0 mL), 130 °C, 24 h. Isolated yields.
tion of the starting material is still of great interest. In the
context of ongoing projects on the modification of purine
analogues,7 herein we report the domino intermolecular
Michael/oxidative cross-coupling reaction of adenines and
nitroolefins to afford purine-fused polycyclic derivatives, which
can be further transformed to purine-fused polycyclic
derivatives with an exocyclic amino group by simple reduction.
time was prolonged to 48 h (Table 1, entry 18). Therefore, the
optimal reaction conditions were found to be CuBr (10 mol %)
as the catalyst, air as the oxidant, and PivOH as an additive in
DMSO at 130 °C for 24 h (Table 1, entry 15).
To evaluate the generality of the adenine component in this
domino reaction, a number of adenines with different
substituents at N9 were examined. As shown in Scheme 2,
the corresponding purine-fused polycyclic derivatives were
obtained in good yields (65−87%). Purine rings bearing
different N9 substituents such as n-butyl, ethyl, isopropyl, allyl,
and benzyl groups all furnished the target purine-fused
polycyclic products 3a−e well (78−87% yield). It is noteworthy
that 2′,3′,5′-tri-O-acetyladenosine (1g) also gave the corre-
sponding product 3g in 65% yield, providing a useful route for
the preparation of polycyclic nucleoside analogues.
To further evaluate the generality of the domino reaction, the
series of nitroolefins 2h−t were investigated under the
optimized reaction conditions (Table 2). The steric hindrance
of the substituent groups was examined, and the substrate with
a substituent group at the para position afforded a higher yield
than those substituted at the ortho and meta positions (Table 2,
entries 2−4). Next, several nitroolefins with different electron-
withdrawing groups on the phenyl ring were examined, and the
corresponding purine-fused tricyclic derivatives were obtained
in moderate to good yields (Table 2, entries 5−8). To our
delight, when nitroolefins with electron-donating groups on the
phenyl ring were tested, the desired tricyclic adducts 3o−q
were obtained with good results (Table 2, entries 9−11, 63−
82% yields). On the basis of the above results (Table 2, entries
1−11), we found that electron-rich nitroolefins show higher
yields than electron-deficient ones (Table 2, entries 10 and 11
RESULTS AND DISCUSSION
■
Initially, 9-butylpurin-6-amine (1a) and (E)-(2-nitrovinyl)-
benzene (2a) were chosen as model substrates to explore the
domino reaction conditions (Table 1). Gratifyingly, when
Cu(OAc)2 was used as a catalyst and PhI(OAc)2 was employed
as an oxidant, the desired purine-fused tricyclic product 3a was
obtained in 41% yield (Table 1, entry 1). Subsequently, O2 was
used as the oxidant, and the product 3a was still obtained in
46% yield (Table 1, entry 2). Then several copper salts were
examined with O2 as the oxidant, and CuBr was the best one
(Table 1, entries 2−5). With CuBr as the catalyst, a series of
oxidants including air, H2O2, and K2S2O8 were tested, and air
was found to give the highest yield (62%; Table 1, entries 6−8).
To further increase the yield of the product, some additives
were tested, and PivOH emerged as the best one (75% yield;
Table 1, entries 9−12). Switching the reaction solvent from
DMF to 1,2-dichloroethane (DCE), CH3CN, DMSO, xylene,
or ethane-1,2-diol (EG) proved that aprotic solvents were
much better than protic solvents, and DMSO gave the highest
yield (85%) with almost complete consumption of the starting
material 1a (Table 1, entries 12−17). When the reaction was
performed at a lower temperature such as 70 °C, only a trace
amount of product 3a was detected even when the reaction
C
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vs entries 4−6 and 8 and entry 9 vs entry 2). In addition,
heteroaryl species, including 2-furanyl and 2-thienyl nitro-
olefins, also underwent the domino reaction to afford the
purine-fused tricyclic products, although the yields were
somewhat low (Table 2, entries 12 and 13). In the case of
the 1-naphthaldehyde-derived nitroolefin, the corresponding
product 3t was obtained in 25% yield (Table 2, entry 14).
However, when aliphatic nitroolefins such as cyclohexyl and n-
butyl nitroolefins were tested, trace amounts of products were
observed. Finally, other Michael acceptors including methyl
acrylate and acrylonitrile were also tested, and no reactions
occurred.
To verify the structure of the products, we tried to grow
crystals of the products suitable for X-ray diffraction analysis.
The structure of purine-fused tricyclic derivative 3j was
unambiguously determined by single-crystal X-ray diffraction
analysis.8 The crystal structure of compound 3j confirmed the
nitro group to be connected to the N1 position of the purine
derivative, indicating that the domino reaction proceeds with
high regioselectivity.
indicating that the CuBr catalyst plays a critical role in the
reaction. Next, when air was replaced by N2, the reaction also
did not occur (Scheme 4, B1), proving that air functions as an
oxidant and that the oxidant is essential for the reaction to
happen. In addition, the reaction did not proceed in the
presence of the radical scavenger TEMPO, and the starting
material nitroolefin 2a was recovered (Scheme 4, C1). Thus, a
radical intermediate may be included in the reaction.
On the basis of the above control experiments, the X-ray
structure of 3g, and previous work,9,10 a proposed mechanism
of the reaction is illustrated in Scheme 5. In the first step, the
Michael addition reaction between adenine 1 and nitroolefin 2
takes place, forming intermediate 5. With the Cu(II) catalyst as
an oxidant, radical cation 6 is generated from intermediate 5 by
a one-electron oxidation. Next, with the help of CuBr and air,
the oxidative cross-coupling reaction forms imine intermediate
7, which subsequently equilibrates to enamine intermediate 8.
Similarly, radical cation 9 is generated by hydride abstraction
with the Cu(II) catalyst. Finally, the oxidative cross-coupling
reaction of intermediate 9 generates the cyclization product 3.
In the case of aliphatic nitroolefins and acrylonitrile, it may be
hard to form the corresponding Michael adduct intermediates,
and the reaction does not occur.
In view of the importance of exocyclic amino groups in
purine-fused polycyclic derivatives, the reduction of the nitro
group in product 3g was tried. As shown in Scheme 3, with the
help of Pd/C, the polycyclic nucleoside 3g was hydrogenated
smoothly, and the desired polycyclic nucleoside 4g with an
exocyclic amino group was obtained in 70% yield.
CONCLUSION
■
We have developed a copper-catalyzed domino Michael/
oxidative cross-coupling reaction of adenines and nitroolefins.
With CuBr as a catalyst and air as an oxidant, a series of purine-
fused polycyclic derivatives with structural diversity were
obtained in good yields. Meanwhile, this method proceeds
with high regioselectivity, and two new C−N bonds are
generated in this domino reaction. Moreover, purine nucleo-
sides with an exocyclic amino group can be easily obtained,
which may lead to potential applications in fluorescence
recognition of various bases in vivo.
Scheme 3. Reduction of 3g To Afford the Polycyclic
Nucleoside with an Exocyclic Amino Group
EXPERIMENTAL SECTION
■
General. All of the reagents and solvents were purchased from
commercial sources and purified commonly before use. DMSO used in
reactions was reagent grade and distilled from CaH2. All of the
reactions were monitored by thin-layer chromatography (TLC). NMR
Next, some control experiments were designed to evaluate
the mechanism of this domino reaction. First, the role of the
copper catalyst was tested. When the reaction was performed in
the absence of CuBr, no product was observed (Scheme 4, A1),
spectra were recorded at 400 MHz for H NMR or 100 MHz for 13C
1
NMR. Chemical shifts (δ) are given in parts per million relative to the
residual proton signals of the deuterated solvent CDCl3 or DMSO for
1H and 13C NMR. Multiplicities are reported as follows: singlet (s),
doublet (d), triplet (t), quartet (q), multiplet (m). High-resolution
mass spectra were recorded using a Q-TOF system, and electrospray
ionization (ESI) was used as the ionization method for the HRMS
measurements. For column chromatography, silica gel (200−300
mesh) was used as the stationary phase. Melting points were recorded
with a micro melting point apparatus and are uncorrected.
Scheme 4. Control Experiments
Typical Procedure for the Domino Reaction. A mixture of
CuBr (10 mol %), PivOH (3.0 equiv), 9-butylpurin-6-amine (1a) (0.3
mmol), (E)-(2-nitrovinyl)benzene (2a) (1.2 equiv), and dry DMSO
(2.0 mL) in a dry round-bottom flask were stirred at 130 °C for 24 h
under a N2 atmosphere, and the reaction was monitored by TLC. After
cooling, the reaction mixture was extracted with ethyl acetate and
water. Then the organic phase was evaporated under reduced pressure,
and the residue was purified by column chromatography on silica gel
(petroleum ether/ethyl acetate) to give the desired product 3a in 85%
yield.
3-Butyl-7-nitro-8-phenyl-3H-imidazo[2,1-i]purine (3a). Yellow
solid (85.6 mg, 85% yield). Mp 223−225 °C. 1H NMR (CDCl3,
400 MHz): δ 10.11 (s, 1H), 8.14 (s, 1H), 8.06 (d, J = 4.8 Hz, 2H),
7.53 (d, J = 3.6 Hz, 3H), 4.40 (t, 2H), 1.98 (m, 2H), 1.41 (m, 2H),
D
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Scheme 5. Proposed Mechanism of the Reaction
1.00 (t, 3H). 13C NMR (DMSO-d6, 100 MHz): δ 149.9, 145.1, 142.9,
141.7, 136.8, 132.0, 130.7, 130.5, 129.1, 128.4, 122.4, 44.1, 31.9, 19.6,
13.8. HRMS: calcd for C17H16N6O2 [M + Na]+ 359.1227, found
359.1229.
3-Butyl-8-(2-chlorophenyl)-7-nitro-3H-imidazo[2,1-i]purine (3h).
Yellow solid (66.8 mg, 60% yield). Mp 220−222 °C. 1H NMR
(CDCl3, 400 MHz): δ 10.10 (s, 1H), 8.16 (s, 1H), 7.61 (d, J = 5.4 Hz,
1H), 7.52 (d, J = 8.0 Hz, 1H), 7.47−7.39 (m, 2H), 4.41 (t, 2H), 1.95
(m, 2H), 1.38 (m, 2H), 0.95 (t, 3H). 13C NMR (CDCl3, 100 MHz): δ
148.1, 143.6, 142.6, 141.6, 135.7, 134.1, 131.4, 131.3, 131.1, 129.5,
126.8, 123.1, 44.6, 32.2, 19.8, 13.5. HRMS: calcd for C17H15ClN6O2
[M + Na]+ 393.0837, found 393.0830.
3-Butyl-8-(3-chlorophenyl)-7-nitro-3H-imidazo[2,1-i]purine (3i).
Yellow solid (71.2 mg, 64% yield). Mp 180−182 °C. 1H NMR
(CDCl3, 400 MHz): δ 9.99 (s, 1H), 8.12 (s, 1H), 7.96 (s, 1H), 7.85 (d,
J = 7.2 Hz, 1H), 7.44−7.36 (m, 2H), 4.35 (t, 2H), 1.91 (m, 2H), 1.34
(m, 2H), 0.93 (t, 3H). 13C NMR (CDCl3, 100 MHz): δ 149.1, 143.6,
141.5, 136.0, 133.9, 132.8, 130.6, 130.5, 129.3, 128.8, 128.5, 122.8,
44.6, 32.1, 19.8, 13.5. HRMS: calcd for C17H15ClN6O2 [M + H]+
371.1018, found 371.1023.
3-Butyl-8-(4-chlorophenyl)-7-nitro-3H-imidazo[2,1-i]purine (3j).
Yellow solid (84.6 mg, 76% yield). Mp 209−210 °C. 1H NMR
(CDCl3, 400 MHz): δ 10.06 (s, 1H), 8.14 (s, 1H), 8.00 (d, J = 8.4 Hz,
2H), 7.85 (d, J = 7.2 Hz, 2H), 4.39 (t, 2H), 1.96 (m, 2H), 1.39 (m,
2H), 0.98 (t, 3H). 13C NMR (CDCl3, 100 MHz): δ 149.7, 143.4,
142.7, 141.6, 136.9, 136.1, 132.1, 129.5, 128.3, 122.9, 44.5, 32.1, 19.8,
13.4. HRMS: calcd for C17H15ClN6O2 [M + H]+ 371.1018, found
371.1011.
3-Butyl-8-(4-fluorophenyl)-7-nitro-3H-imidazo[2,1-i]purine (3k).
Yellow solid (82.8 mg, 78% yield). Mp 193−195 °C. 1H NMR
(CDCl3, 400 MHz): δ 10.02 (s, 1H), 8.13 (s, 1H), 8.03 (q, 2H), 7.14
(t, 2H), 4.36 (t, 2H), 1.92 (m, 2H), 1.36 (m, 2H), 0.95 (t, 3H). 13C
NMR (CDCl3, 100 MHz): δ 165.4, 162.9, 157.9, 149.9, 143.5, 141.6,
136.2, 133.1, 133.0, 128.4, 127.1, 127.1, 115.3, 115.1, 44.6, 32.2, 19.8,
13.5. HRMS: calcd for C17H15FN6O2 [M + H]+ 355.1313, found
355.1319.
3-Ethyl-7-nitro-8-phenyl-3H-imidazo[2,1-i]purine (3b). Yellow
solid (79.5 mg, 86% yield). Mp 215−217 °C. 1H NMR (CDCl3,
400 MHz): δ 10.09 (s, 1H), 8.15 (s, 1H), 8.05 (t, 2H), 5.51 (d, J = 5.2
Hz, 3H), 4.45 (q, 2H), 1.64 (t, 3H). 13C NMR (CDCl3, 100 MHz): δ
151.0, 142.9, 141.7, 136.2, 131.1, 130.8, 130.7, 128.1, 123.1, 39.9, 15.6.
HRMS: calcd for C15H12N6O2 [M + Na]+ 311.0914, found 331.0911.
3-Isopropyl-7-nitro-8-phenyl-3H-imidazo[2,1-i]purine (3c). Yel-
low solid (84.0 mg, 87% yield). Mp 205−207 °C. 1H NMR
(CDCl3, 400 MHz): δ 10.01 (s, 1H), 8.19 (s, 1H), 7.97 (q, 2H),
7.46 (m, 3H), 4.97 (m, 1H), 1.67 (s, 3H), 1.66 (s, 3H). 13C NMR
(CDCl3, 100 MHz): δ 150.9, 141.6, 141.3, 135.9, 131.0, 130.7, 130.6,
128.5, 128.0, 123.2, 48.6, 22.7. HRMS: calcd for C16H14N6O2 [M +
Na]+ 345.1070, found 345.1069.
3-Allyl-7-nitro-8-phenyl-3H-imidazo[2,1-i]purine (3d). Yellow
solid (74.9 mg, 78% yield). Mp 202−204 °C. 1H NMR (CDCl3,
400 MHz): δ 10.10 (s, 1H), 8.15 (s, 1H), 8.05 (d, J = 5.6 Hz, 2H),
7.53 (s, 3H), 6.11 (m, 1H), 5.40 (d, J = 10.4 Hz, 1H), 5.30 (d, J = 17.2
Hz, 1H), 5.01 (d, J = 5.6 Hz, 2H). 13C NMR (CDCl3, 100 MHz): δ
151.0, 143.2, 141.6, 136.4, 131.1, 131.0, 130.8, 130.7, 128.1, 122.9,
119.9, 46.7. HRMS: calcd for C16H12N6O2 [M + Na]+ 343.0914, found
343.0906.
3-Benzyl-7-nitro-8-phenyl-3H-imidazo[2,1-i]purine (3e). Yellow
solid (88.8 mg, 80% yield). Mp 229−231 °C. 1H NMR (CDCl3,
400 MHz): δ 10.12 (s, 1H), 8.14 (s, 1H), 8.05 (d, J = 5.2 Hz, 2H),
7.53 (s, 3H), 7.36 (t, 5H), 5.56 (s, 2H). 13C NMR (CDCl3, 100
MHz): δ 151.1, 143.2, 142.6, 141.6, 136.5, 134.7, 131.0, 130.8, 130.7,
129.3, 128.9, 128.1, 127.9, 123.0, 48.3. HRMS: calcd for C20H14N6O2
[M + H]+ 371.1251, found 371.1243.
2-((7-Nitro-8-phenyl-3H-imidazo[2,1-i]purin-3-yl)methoxy)ethyl
Acetate (3f). Yellow solid (96.2 mg, 81% yield). Mp 145−147 °C. 1H
NMR (CDCl3, 400 MHz): δ 10.14 (s, 1H), 8.30 (s, 1H), 8.05 (m,
2H), 7.53 (m, 3H), 5.83 (s, 2H), 4.22 (t, 2H), 3.82 (t, 2H), 2.05 (s,
3H). 13C NMR (CDCl3, 100 MHz): δ 170.7, 150.9, 143.7, 142.5,
141.3, 136.9, 130.8, 130.8, 130.6, 128.6, 128.1, 122.8, 73.5, 68.0, 62.7,
20.8. HRMS: calcd for C18H16N6O5 [M + H]+ 397.1255, found
397.1247.
8-(4-Bromophenyl)-3-butyl-7-nitro-3H-imidazo[2,1-i]purine (3l).
Yellow solid (99.6 mg, 80% yield). Mp 225−227 °C. 1H NMR
(CDCl3, 400 MHz): δ 10.07 (s, 1H), 8.15 (s, 1H), 7.93 (d, J = 8.8 Hz,
2H), 7.63 (d, J = 8.4 Hz, 2H), 4.39 (t, 2H), 1.95 (m, 2H), 1.38 (m,
2H), 0.98 (t, 3H). 13C NMR (CDCl3, 100 MHz): δ 149.8, 143.5,
141.7, 136.2, 132.3, 131.4, 129.9, 125.6, 44.6, 32.2, 19.8, 13.5. HRMS:
calcd for C17H15BrN6O2 [M + H]+ 415.0513, found 415.0513.
8-(3-Bromophenyl)-3-butyl-7-nitro-3H-imidazo[2,1-i]purine
1
(3m). Yellow solid (82.2 mg, 66% yield). Mp 170−172 °C. H NMR
(2R,3R,4R,5R)-2-(Acetoxymethyl)-5-(7-nitro-8-phenyl-3H-
(CDCl3, 400 MHz): δ 10.01 (s, 1H), 8.13 (d, J = 1.6 Hz, 2H), 7.92 (d,
J = 7.6 Hz, 1H), 7.59 (d, J = 9.2 Hz, 1H), 7.34 (t, 1H), 4.36 (t, 2H),
1.92 (m, 2H), 1.35 (m, 2H), 0.94 (t, 3H). 13C NMR (CDCl3, 100
MHz): δ 149.1, 143.6, 142.8, 141.6, 136.1, 133.6, 133.4, 133.0, 129.6,
129.3, 128.5, 122.9, 121.9, 44.6, 32.2, 19.8, 13.5. HRMS: calcd for
C17H15BrN6O2 [M + H]+ 415.0513, found 415.0518.
imidazo[2,1-i]purin-3-yl)tetrahydrofuran-3,4-diyl Diacetate (3g).
1
Yellow oil (104.9 mg, 65% yield). H NMR (CDCl3, 400 MHz): δ
10.13 (s, 1H), 8.34 (s, 1H), 8.04 (t, 2H), 7.53 (d, J = 7.2 Hz, 3H), 6.32
(d, J = 5.2 Hz, 1H), 5.97 (t, 1H), 5.64 (t, 1H), 4.56−4.51 (q, 1H),
4.51−4.40 (m, 2H), 2.19 (s, 3H), 2.16 (s, 3H), 2.12 (s, 3H). 13C NMR
(CDCl3, 100 MHz): δ 170.4, 169.7, 169.4, 150.9, 142.1, 141.7, 141.2,
136.8, 130.9, 130.8, 130.6, 128.6, 128.1, 123.8, 87.1, 80.5, 73.5, 70.4,
63.0, 20.8, 20.6, 20.4. HRMS: calcd for C24H22N6O9 [M + Na]+
561.1340, found 561.1333.
3-Butyl-7-nitro-8-(4-nitrophenyl)-3H-imidazo[2,1-i]purine (3n).
Yellow solid (68.6 mg, 60% yield). Mp 230−232 °C. 1H NMR
(CDCl3, 400 MHz): δ 10.09 (d, J = 2.4 Hz, 1H), 8.36 (d, J = 8.8 Hz,
2H), 8.22 (d, J = 8.8 Hz, 2H), 8.18 (s, 1H), 4.43 (t, 2H), 1.99 (m,
E
dx.doi.org/10.1021/jo4025489 | J. Org. Chem. XXXX, XXX, XXX−XXX

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2H), 1.41 (m, 2H), 1.00 (t, 3H). 13C NMR (CDCl3, 100 MHz): δ
148.8, 148.1, 143.6, 142.8, 141.7, 137.3, 135.9, 131.7, 123.2, 44.6, 32.2,
19.8, 13.4. HRMS: calcd for C17H15N7O4 [M + Na]+ 404.1078, found
404.1069.
3-Butyl-8-(2-methoxyphenyl)-7-nitro-3H-imidazo[2,1-i]purine
(3o). Yellow oil (69.2 mg, 63% yield). 1H NMR (CDCl3, 400 MHz): δ
10.07 (s, 1H), 8.12 (s, 1H), 7.71 (q, 1H), 7.50 (m, 1H), 7.11 (t, 1H),
7.01 (d, J = 8.4 Hz, 1H), 4.39 (t, 2H), 3.82 (s, 3H), 1.96 (m, 2H), 1.38
(m, 2H), 0.98 (t, 3H). 13C NMR (CDCl3, 100 MHz): δ 157.8, 147.6,
143.0, 142.3, 141.5, 135.8, 131.8, 131.2, 123.0, 121.2, 120.6, 110.8,
55.6, 44.5, 32.2, 19.8, 13.4. HRMS: calcd for C18H18N6O3 [M + Na]+
389.1333, found 389.1328.
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of 1H and 13C NMR spectra of compounds 3a−t and 4g
and the X-ray crystal structure of 3j (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*Fax: (+) (+86) 373-3329276. E-mail: quguir@sina.com.
*E-mail: guohm518@hotmail.com.
■
Notes
3-Butyl-8-(4-methoxyphenyl)-7-nitro-3H-imidazo[2,1-i]purine
1
The authors declare no competing financial interest.
(3p). Yellow solid (87.8 mg, 80% yield). Mp 209−211 °C. H NMR
(CDCl3, 400 MHz): δ 10.07 (s, 1H), 8.11 (s, 1H), 8.09 (t, 2H), 7.01
(d, J = 6.8 Hz, 2H), 4.37 (t, 2H), 3.88 (s, 3H), 1.95 (m, 2H), 1.38 (m,
2H), 0.97 (t, 3H). 13C NMR (CDCl3, 100 MHz): δ 161.8, 151.2,
143.2, 142.8, 141.7, 136.4, 132.7, 123.2, 122.8, 113.5, 77.4, 77.3, 77.1,
76.8, 55.5, 44.5, 32.2, 19.8, 13.5. HRMS: calcd for C18H18N6O3 [M +
H]+ 367.1513, found 367.1514.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of China (Grants 21072047, 21172059,
21272059, 21202039, and 21372066), the Excellent Youth
Foundation of Henan Scientific Committee (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 Research Fund for the Doctoral
Program of Higher Education of China (20124104110006),
and the Program for Science & Technology Innovation Talents
in Universities of Henan Province (13HASTIT013).
3-Butyl-7-nitro-8-(p-tolyl)-3H-imidazo[2,1-i]purine (3q). Yellow
1
solid (86.1 mg, 82% yield). Mp 206−208 °C. H NMR (DMSO-d6,
400 MHz): δ 9.88 (s, 1H), 8.58 (s, 1H), 7.81 (d, J = 3.6 Hz, 2H), 7.33
(d, J = 7.6 Hz, 2H), 4.36 (t, 2H), 2.39 (s, 3H), 1.87 (t, 2H), 1.29 (m,
2H), 0.90 (t, 3H). 13C NMR (DMSO-d6, 100 MHz): δ 150.1, 145.1,
142.9, 141.7, 140.8, 136.9, 130.6, 129.1, 129.0, 128.9, 122.3, 44.1, 31.9,
21.5, 19.6, 13.7. HRMS: calcd for C18H18N6O2 [M + H]+ 351.1564,
found 351.1556.
3-Butyl-8-(furan-2-yl)-7-nitro-3H-imidazo[2,1-i]purine (3r). Yel-
low solid (40.1 mg, 41% yield). Mp 220−222 °C. 1H NMR
(CDCl3, 400 MHz): δ 10.11 (s, 1H), 8.15 (s, 1H), 8.00 (d, J = 3.2
Hz, 1H), 7.79 (s, 1H), 6.69 (d, J = 1.6 Hz, 1H), 4.38 (t, 2H), 1.96 (m,
2H), 1.39 (m, 2H), 0.98 (t, 3H). 13C NMR (CDCl3, 100 MHz): δ
146.8, 145.4, 143.3, 142.3, 140.5, 136.2, 120.0, 112.8, 44.5, 32.2, 19.8,
13.5. HRMS: calcd for C15H14N6O3 [M + Na]+ 349.1020, found
349.1015.
3-Butyl-7-nitro-8-(thiophen-2-yl)-3H-imidazo[2,1-i]purine (3s).
Yellow solid (31.8 mg, 31% yield). Mp 239−241 °C. 1H NMR
(CDCl3, 400 MHz): δ 10.10 (s, 1H), 8.65 (dd, J = 3.6, 0.8 Hz, 1H),
8.11 (s, 1H), 7.74−7.70 (m, 1H), 7.29−7.24 (m, 1H), 4.38 (t, J = 7.2
Hz, 2H), 2.04−1.93 (m, 2H), 1.43−1.38 (m, 2H), 1.00 (t, J = 7.2 Hz,
3H). 13C NMR (CDCl3, 100 MHz): δ 145.0, 143.1, 136.4, 134.5,
133.7, 133.2, 128.2, 44.5, 32.2, 19.8, 13.4. HRMS: calcd for
C15H14N6O2S [M + Na]+ 365.0791, found 365.0792.
3-Butyl-8-(naphthalen-1-yl)-7-nitro-3H-imidazo[2,1-i]purine (3t).
Yellow solid (28.9 mg, 25% yield). Mp 217−218 °C. 1H NMR
(CDCl3, 400 MHz): δ 10.18 (s, 1H), 8.16 (s, 1H), 8.03 (d, J = 8.4 Hz,
1H), 7.95 (d, J = 8.0 Hz, 1H), 7.79 (dd, J = 7.8, 0.8 Hz, 1H), 7.76 (d, J
= 8.0 Hz, 1H), 7.61 (dd, J = 8.4, 7.2 Hz, 1H), 7.54−7.50 (m, 1H),
7.47−7.42 (m, 1H), 4.42 (t, J = 7.2 Hz, 2H), 2.00−1.96 (m, 2H),
1.44−1.38 (m, 2H), 1.00 (t, J = 7.2 Hz, 3H). 13C NMR (CDCl3, 100
MHz): δ 150.3, 143.4, 141.8, 136.0, 133.4, 131.1, 130.7, 129.3, 128.9,
128.6, 127.0, 126.2, 125.0, 44.6, 32.2, 19.8, 13.4. HRMS: calcd for
C21H18N6O2 [M + Na]+ 409.1383, found 409.1380.
Reduction Reaction of 3g To Give (2R,3R,4R,5R)-2-(Acetox-
ymethyl)-5-(7-amino-8-phenyl-3H-imidazo[2,1-i]purin-3-yl)-
tetrahydrofuran-3,4-diyl Diacetate (4g). A solution of compound
3g (0.2 mmol, 100.2 mg) in MeOH (10.0 mL) was treated with Pd/C
(10 mol %, 2.12 mg) under H2 (1.0 atm) and stirred for 24 h at room
temperature. After completion of the reaction, the reaction mixture
was filtered through a Celite pad and washed with MeOH. The filtrate
was evaporated under reduced pressure, and the residue was purified
by column chromatography on silica gel (eluent: CH2Cl2/MeOH =
100:1−50:1) to give the desired product 4g as a pale-yellow solid in
70% yield. 1H NMR (CDCl3, 400 MHz): δ 8.81 (s, 1H), 8.09 (s, 1H),
8.06 (d, J = 7.2 Hz, 2H), 7.48 (t, 2H), 7.34 (t, 1H), 6.23 (d, J = 5.2 Hz,
1H), 6.06 (t, 1H), 5.71 (t, 1H), 4.50 (d, J = 9.2 Hz, 2H), 4.42−4.38 (q,
1H), 4.56−3.49 (m, 2H), 2.17 (s, 3H), 2.14 (s, 3H), 2.11 (s, 3H).
HRMS: calcd for C24H24N6O7 [M + Na]+ 531.1599, found 531.1599.
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