Copper-catalyzed intramolecular cyclization of N-propargyl-adenine: Synthesis of purine-fused tricyclics

Article abstract of DOI:10.1021/jo5001687

A novel protocol to construct fluorescent purine-fused tricyclic products via intramolecular cyclization of N-propargyl-adenine has been developed. With CuBr as the catalyst, a series of purine-fused tricyclic products were obtained in good to excellent yields (19 examples, 75-89% yields). When R₂ was a hydrogen atom in N-propargyl-adenines, the reactions only afforded the endocyclic double bond products. When R₂ was an aryl group, the electron-donating groups favored the endocyclic double bond products, while the electron-withdrawing groups favored the exocyclic double bond products.

Full text of DOI:10.1021/jo5001687

Note
pubs.acs.org/joc
Copper-Catalyzed Intramolecular Cyclization of N‑Propargyl-
Adenine: Synthesis of Purine-Fused Tricyclics
Ren-Long Li,† Lei Liang,† Ming-Sheng Xie,† Gui-Rong Qu,*,† Hong-Ying Niu,‡ 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, PR China
‡School of Chemistry and Chemical Engineering, Henan Institute of Science and Technology, Xinxiang, Henan 453003, PR China
S
* Supporting Information
ABSTRACT: A novel protocol to construct fluorescent
purine-fused tricyclic products via intramolecular cyclization
of N-propargyl-adenine has been developed. With CuBr as the
catalyst, a series of purine-fused tricyclic products were
obtained in good to excellent yields (19 examples, 75−89%
yields). When R2 was a hydrogen atom in N-propargyl-
adenines, the reactions only afforded the endocyclic double
bond products. When R2 was an aryl group, the electron-
donating groups favored the endocyclic double bond products,
while the electron-withdrawing groups favored the exocyclic
double bond products.
urine-fused tricyclic and polycyclic derivatives are an
important class of nitrogen-containing heterocycles that
Scheme 1. Synthesis of Purine-Fused Tricyclic Derivatives
Starting from N-Propargyl-adenine
P
have attracted considerable attention in biochemistry, molec-
ular biology, and toxicology.1 For example, purine-fused
tricyclic 1,N6-ethenoadenine (Figure 1) has been widely studied
nucleophilic attack of N1 to allenamine through C would lead
to the formation of two purine-fused tricyclic products 2 and 3.
In the context of ongoing projects on the modification of
purine analogues,7,8 herein we report a useful and facile
alternative process for the synthesis of fluorescent purine-fused
tricyclic derivatives by using substituted propargyl-adenine
compounds as starting material.9
Initially, we conducted our study by treating N-propargyl-9-
benzyl-adenine 1a with CuBr in the presence of CsCO3 in
dioxane (Table 1). To our delight, the cyclization reaction
occurred, and purine-fused tricyclic product 2a was formed,
though the yield was not satisfied (entry 1). Next, some
quaternary ammonium salts such as n-Bu4NBr, Me4NBr, or
Me4NCl were added into the reaction (entries 2−5).10 The
results showed that n-Bu4NBr was the best one affording
product 2a with 86% yield (entry 4). When the catalyst loading
Figure 1. Selected examples of purine-fused tricyclics exhibited high
fluorescence properties.
because of their excellent fluorescence properties.2 And 1,N6-
ethenoadenine 3′,5′-monophosphate is a highly fluorescent
probe.2f,g Thus, chemists have tried to synthesize different
purine-fused polycyclics and studied their fluorescence proper-
ties and biological activities.3 The classical approach for the
synthesis of purine-fused polycyclics is via the reaction of
haloacetaldehyde with adenine or adenosine.4 Although great
endeavor has been devoted to the synthesis of purine-fused
polycyclics, the structure diversity of purine-fused polycyclic
derivatives is still very limited. Therefore, searching for a new
approach for the synthesis of purine-fused polycyclic with
structure diversity is highly desirable.
We proposed the purine-fused tricyclics could be constructed
as follows (Scheme 1): allenamine intermediate A might be
generated from substrate 1 and a base,5,6 and then intermediate
B, the tautomer of A, could be activated by a catalyst, and the
Received: January 24, 2014
Published: March 28, 2014
© 2014 American Chemical Society
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Note
a
Table 1. Optimization of the Reaction Conditions
Table 2. Effect of N9-Substitutent in the N-Propargyl-
a
adenine
b
entry
catalyst (x)
base
additive
yield (%)
1
2
3
4
5
6
CuBr (20)
CuBr (20)
CuBr (20)
CuBr (20)
CuBr (20)
CuBr (10)
CuBr (10)
CuBr (10)
CuBr (10)
CuBr (10)
CuBr (10)
CuBr (10)
CuCl (10)
CuI (10)
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Na2CO3
K2CO3
−
55
n-Bu4NI
48
Me4NBr
25
Me4NCl
32
n-Bu4NBr
n-Bu4NBr
n-Bu4NBr
n-Bu4NBr
n-Bu4NBr
n-Bu4NBr
n-Bu4NBr
n-Bu4NBr
n-Bu4NBr
n-Bu4NBr
n-Bu4NBr
86
87
c
7
52
d
8
e
60
9
72
10
11
12
13
14
15
60
72
t-BuOK
Cs2CO3
Cs2CO3
Cs2CO3
trace
68
79
CuBr2 (10)
trace
a
The reactions were carried out with 1a (0.3 mmol), catalyst, base (0.3
mmol), solvent (2.0 mL), additive (1.0 equiv) in a Schlenk tube at 100
b
c
°C for 10 h under N2 atmosphere. Isolated yield. Toluene was used
as the solvent. MeCN was used as the solvent. DMF was used as the
solvent.
d
e
was lowered to 10 mol %, the reaction also proceeded well,
giving the product 2a with 87% yield (entry 6). The screening
of solvents showed that dioxane was the suitable one (entries
6−9). Next, a range of bases were examined, and Cs2CO3
emerged as the best choice (entries 10−12). Subsequently,
several copper salts were probed (entries 13−15), and for
CuCl2, Cu(OAc)2, Cu(OTf)2, CuSO4, trace amounts of
products were obtained. It was found that Cu(I) exhibited
better catalytic activity than Cu(II), and CuBr was the most
suitable copper source. Finally, the optimal conditions were
determined to be 10 mol % of CuBr, 1.0 equiv of CsCO3, and 1
equiv of n-Bu4NBr in dioxane (entry 6).
With the optimized conditions (Table 1, entry 6) in hand,
the scope of this cyclization reaction was investigated. As shown
in Table 2, a series of N9-substituted substrates, including alkyl,
benzyl, allyl, and sugar groups, were subjected to the optimized
reaction conditions. The results showed that all the substrates
could be transformed into the purine-fused tricyclics in good
yields (2a−2h, 76−88% yields). Notably, the allyl substituted
1e and glycosidic substituted 1h are suitable substrates for the
reactions (78% yield for 2e, 87% yield for 2h), which offers an
ideal opportunity for further synthetic manipulation.
Subsequently, various N-propargyl-adenines 1i−1s with
different aryl groups at the terminal position of alkynyl part
were synthesized via Sonogashira coupling reactions. As shown
in Table 3, when Ar was phenyl group, the corresponding
purine-fused tricyclic products 2i and 3i were obtained in 88%
total yield, in which the endocyclic double bond product 2i was
the major form (entry 1). Next, a series of electron-donating
groups at the benzene ring in the alkenyl part of 9-benzyl-
adenines were evaluated (entries 2−7). When ortho- or meta-
methyl substituted substrates were explored, the reactions
proceeded well, affording purine-fused tricyclic products in
excellent yields, in which the endocyclic double bond products
2j and 2k were the major form (entries 2−3). Meanwhile, the
a
The reactions were carried out with 1 (0.3 mmol), CuBr (10 mol %),
CsCO3 (0.3 mmol), dioxane (2.0 mL), n-Bu4NBr (0.3 mmol) in a
b
Schlenk tube at 100 °C for 10 h under N2 atmosphere. Isolated yield.
3,5-dimethylphenyl substituted substrate 1l could also be
tolerated in the reaction, giving the endocyclic double bond
product 2l as the major form (entry 4). Furthermore, several
alkoxy groups (OCH3, OEt) substituted substrates were tested,
and the cyclization reactions worked well, affording the
corresponding purine-fused tricyclic products in 85−88%
yields, in which the endocyclic double bond products 2m, 2n,
2o were the major form, respectively (entries 5−7). Then,
several electron-withdrawing groups at the benzene ring in the
alkenyl part of 9-benzyl-adenines were examined (entries 8−
10). To our delight, these substrates (1p−1r) could afford the
cyclization products in good yields (75−88% yields). Contra-
rily, the exocyclic double bond products 3p, 3q, 3r were the
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Note
survive this reaction well (entry 11). Take product 3p as the
representative product; the structure of 3p with exocyclic Z-
Table 3. Effect of Aryl Groups at the Terminal Position of
Alkynyl Part in N-Propargyl-adenine
a
1
form double bond was confirmed by the H, 13C, and NOESY
spectra (see Supporting Information for details). It should be
noted that the isomerization of products 2 and 3 could not
occur under the optimized reaction conditions. Meanwhile, the
endocyclic double product 2 and the exocyclic double product
3 could be separated through column chromatography. In
addition, the fluorescence properties of selected products (2i,
2j, 2m) were studied, and the results indicated that these
products showed moderate fluorescence intensity (see
Supporting Information for details).
In conclusion, we have developed a new approach to
construct purine-fused tricyclic products via copper-catalyzed
intramolecular cyclization of N-propargyl-adenine. With CuBr
as the catalyst, a series of purine-fused tricyclic products were
obtained in good to excellent yields (19 examples, 75−89%
yields). Meanwhile, the cyclization reactions only afforded the
endocyclic double bond products with N-propargyl-adenines as
the starting materials. As for the electronic effects of the
substituents at the benzene ring in the alkenyl part, the
electron-donating groups favored the endocyclic double bond
products. Contrarily, the electron-withdrawing groups favored
the exocyclic double bond products.
EXPERIMENTAL SECTION
General Methods. Melting points were recorded with a melting
point microapparatus and are uncorrected. NMR spectra were
■
1
recorded with a 400 NMR spectrometer for H NMR, 100 MHz for
13C NMR. Chemical shifts δ were given in ppm relative to
tetramethylsilane in CDCl3 or (CD3)2SO for 1H 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. All reactions were set up in air (with no use of a
glovebox) and carried out in a sealed pressure tube.
Typical Procedures. For the Synthesis of 2a−2h. In a sealed
tube, 1a−1h (0.3 mmol), CuBr (4.3 mg, 0.03 mmol), CsCO3 (97.7
mg, 0.3 mmol), n-Bu4NBr (96.7 mg, 0.3 mmol), and then dioxane (2.0
mL) were added, and the reaction mixture was heated at 100 °C for 10
h. After cooling down to room temperature, the mixture was diluted
with brine (3.0 mL) and extracted with EtOAc (3 × 3.0 mL). Then,
the organic layer was collected and dried over anhydrous Na2SO4,
filtered and concentrated under reduced pressure. The crude material
was purified by column chromatography on silica gel (eluting with
Pet/EtOAc mixtures) to give the desired products.
For the Synthesis of 2i−2s and 3i−3s. In a sealed tube, 1i−1s (0.3
mmol), CuBr (4.3 mg, 0.03 mmol), CsCO3 (48.4 mg, 0.15 mmol), n-
Bu4NBr (96.7 mg, 0.3 mmol), and then dioxane (2.0 mL) were added,
and the reaction mixture was heated at 100 °C for 10 h. After cooling
down to room temperature, the mixture was diluted with brine (3.0
mL) and extracted with EtOAc (3 × 3.0 mL). Then, the organic layer
was collected and dried over anhydrous Na2SO4, filtered and
concentrated under reduced pressure. The crude material was purified
by column chromatography on silica gel (eluting with Pet/EtOAc
mixtures) to give the desired products.
For the Synthesis of Starting Materials 1a−1h.11,12 6-Chloro-9-
substituent-purine (3.0 mmol), propargylic amide (3.6 mmol), Et3N
(3.6 mmol), and ethanol (10.0 mL) were added in a 50 mL tube. The
tube was refluxed in a 90 °C bath and stirred for 6 h. After cooling
down to room temperature, the mixture was diluted with water and
then extracted with EtOAc. The extracts were combined, washed with
brine, and then dried over anhydrous Na2SO4. The crude material was
purified by column chromatography on silica gel (eluting with Pet/
EtOAc mixtures) to give the 6-proargylic-9-substituent-adenine.
For the Synthesis of Starting Materials 1i−1s.11,12 6-Proargylic-9-
benzyl-adenine (1.5 mmol), iodobenzene (2.25 mmol), Pd(PPh3)2Cl2
(5 mol %), CuI (10 mol %), and Et3N (5.0 mL) were added in a 50
a
The reactions were carried out with 1 (0.3 mmol), CuBr (10 mol %),
CsCO3 (0.15 mmol), dioxane (2.0 mL), n-Bu4NBr (0.3 mmol) in a
b
Schlenk tube at 100 °C for 10 h under N2 atmosphere. Isolated yield.
c
The Z-configuration of product 3p was confirmed by NOESY
spectrum.
major form (entries 8−10). Particularly noteworthy is that the
terminal alkynes with heterocyclic connections could also
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Note
mL tube. The tube was stirred for 12 h at 35 °C. After cooling down to
room temperature, the mixture was diluted with water and then
extracted with EtOAc. The extracts were combined, washed with brine,
and then dried over anhydrous Na2SO4. The crude material was
purified by column chromatography on silica gel (eluting with Pet/
EtOAc mixtures) to give the 6-proargylic-9-substituent-adenine.
3-Benzyl-7-methyl-3H-imidazo[2,1-i]purine (2a). Yellow solid
(68.7 mg, 87%): mp 195−197 °C; 1H NMR (400 MHz,
(CD3)2SO) δ 8.97 (s, 1H), 8.39 (s, 1H), 7.29−7.22 (m, 6H), 5.50
(s, 2H), 3.34 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 135.5, 133.3,
131.0, 128.8, 128.1, 127.4, 47.6, 9.1; HRMS calcd for C15H14N5 [M +
H+] 264.1244, found 264.1236; IR (KBr) νmax 3054, 2975, 2924, 1637,
1371 cm−1.
3-Ethyl-7-methyl-3H-imidazo[2,1-i]purine (2b). Brown oil (52.5
mg, 88%): 1H NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 7.96 (s, 1H),
7.37 (s, 1H), 7.36 (q, J = 7.2 Hz, 2H), 2.59 (s, 3H), 1.59 (q, J = 7.2
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 139.7, 138.6, 133.0, 131.0,
123.7, 118.9, 39.4, 15.7, 9.2; HRMS calcd for C10H11N5Na [M + Na+]
224. 0907, found 224. 0899; IR (KBr) νmax 2961, 2874, 1679, 1371
cm−1.
3,7-Dibenzyl-3H-imidazo[2,1-i]purine (2i). Brown oil (88.6 mg,
87.1%): H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.93 (s, 1H),
1
7.46 (s, 1H), 7.31−7.23 (m, 8H), 7.21 (s, 1H), 7.19 (s, 1H), 5.40 (s,
2H), 4.31 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 140.3, 138.8,
136.1, 135.4, 133.6, 132.3, 128.9, 128.3, 128.1, 127.4, 127.1, 47.6, 30.4;
HRMS calcd for C21H18N5 [M + H+] 340.1557, found 340.1550; IR
(KBr) νmax 3100, 3029, 2923, 1640, 1374 cm−1.
3-Benzyl-7-benzylidene-7,8-dihydro-3H-imidazo[2,1-i]purine (3i).
1
Light yellow solid (0.9 mg, 0.9%): mp 141−143 °C; H NMR (400
MHz, CDCl3) δ 8.64 (s, 1H), 7.91 (s, 1H), 7.34−7.23 (m, 8H), 7.25−
7.20 (m, 3H), 5.44 (s, 1H), 4.12 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 148.0, 141.3, 140.3, 139.0, 135.5, 134.8, 129.1, 129.0, 128.5,
128.3, 127.5, 126.4, 123.3, 107.6, 47.7, 35.6; HRMS calcd for
C21H18N5 [M + H+] 340.1557, found 340.1561; IR (KBr) νmax
3061, 3026, 2923, 1638, 1372, 694 cm−1.
3-Benzyl-7-(2-methylbenzyl)-3H-imidazo[2,1-i]purine (2j). Brown
1
oil (86.7 mg, 81.9%): H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H),
7.97 (s, 1H), 7.35−7.27 (m, 6H), 7.25−7.19 (m, 2H), 7.13 (d, J = 7.2
Hz, 1H), 6.99 (d, J = 7.6 Hz, 1H), 5.46 (s, 2H), 4.23 (s, 2H), 2.38 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 140.4, 136.4, 135.4, 134.2,
133.7, 132.6, 130.7, 129.0, 128.6, 128.4, 127.6, 127.3, 126.5, 123.7,
121.5, 47.6, 28.2, 19.5; HRMS calcd for C22H19N5Na [M + Na+]
376.1533, found 376.1529; IR (KBr) νmax 3065, 2924, 1641, 1376, 741
cm−1.
3-Benzyl-7-(2-methylbenzylidene)-7,8-dihydro-3H-imidazo[2,1-i]-
purine (3j). Brown oil (7.5 mg, 7.1%): 1H NMR (400 MHz, CDCl3) δ
8.54 (s, 1H), 7.86 (s, 1H), 7.26 (d, J = 7.2 Hz, 2H), 7.19 (d, J = 5.2
Hz, 4H), 7.12 (s, 3H), 6.95 (s, 1H), 5.37 (s, 2H), 4.13 (s, 1H) 2.25 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 147.8, 141.3, 140.3, 139.2,
137.2, 136.6, 135.5, 134.8, 130.3, 130.0, 129.0, 128.4, 127.5, 126.7,
126.1, 123.3, 107.6, 47.7, 33.4, 19.5; HRMS calcd for C22H20N5 [M +
H+] 354.1713, found 354.1706; IR (KBr) νmax 3084, 3030, 2944, 1640,
1375, 695 cm−1.
3-Isopropyl-7-methyl-3H-imidazo[2,1-i]purine (2c). Brown oil
1
(54.9 mg, 85%): H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 7.99
(s, 1H), 7.32 (s, 1H), 4.94−4.87 (m, 1H), 2.56 (s, 3H), 1.64 (d, J = 6.8
Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 138.3, 137.8, 132.8, 130.8,
123.8, 118.9, 47.7, 22.8, 9.2; HRMS calcd for C11H14N5 [M + H+]
216.1244, found 216.1237; IR (KBr) νmax 2969, 2933, 2877, 1638,
1370 cm−1.
3-(Sec-butyl)-7-methyl-3H-imidazo[2,1-i]purine (2d). Brown oil
(57.7 mg, 84%): 1H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 7.96 (s,
1H), 7.51 (s, 1H), 4.68−4.60 (m, 1H), 2.51 (s, 3H), 2.07−1.90 (m,
2H), 1.62 (d, J = 6.8 Hz, 3H), 0.85 (t, J = 5.4 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 142.8, 140.9, 139.4, 138.9, 134.3, 123.0, 107.4, 53.6,
29.8, 20.8, 14.1, 10.6; HRMS calcd for C12H16N5 [M + H+] 230.1400,
found 230.1401; IR (KBr) νmax 2969, 2933, 2877, 1638, 1370 cm−1.
3-Allyl-7-methyl-3H-imidazo[2,1-i]purine (2e). White solid (49.9
3-Benzyl-7-(3-methylbenzyl)-3H-imidazo[2,1-i]purine (2k). Brown
1
oil (83.9 mg, 79.2%): H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H),
1
7.94 (s, 1H), 7.46 (s, 1H), 7.31−7.16 (m, 6H), 7.05 (d, J = 7.6 Hz,
1H), 7.00 (d, J = 6.0 Hz, 2H), 5.41 (s, 2H), 4.27 (s, 2H), 2.28 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 141.7, 140.4, 138.9, 138.7, 136.0,
135.4, 133.8, 132.1, 129.0, 128.9, 128.8, 128.4, 127.9, 127.5, 125.2,
123.4, 122.1, 47.7, 30.3, 21.3; HRMS calcd for C22H19N5Na [M +
Na+] 376.1533, found 376.1528; IR (KBr) νmax 3135, 3029, 2941,
1640, 1371, 766 cm−1.
mg, 78%): mp 101−103 °C; H NMR (400 MHz, CDCl3) δ 8.77 (s,
1H), 8.21 (s, 1H), 7.54 (s, 1H), 6.12−6.03 (m, 1H), 5.35 (d, J = 10.4
Hz, 1H), 5.23 (d, J = 16.8 Hz, 1H), 5.02−4.98 (m, 2H), 2.68 (s, 3H);
13C NMR (100 MHz, (CD3)2SO) δ 141.3, 138.6, 135.4, 133.7, 130.3,
122.7, 120.3, 117.8, 108.6, 46.0, 9.2; HRMS calcd for C11H12N5 [M +
H+] 214.1087, found 214.1083; IR (KBr) νmax 3077, 2920, 1639, 1369
cm−1.
3-Benzyl-7-(3-methylbenzylidene)-7,8-dihydro-3H-imidazo[2,1-i]-
purine (3k). Orange solid (8.3 mg, 7.8%): mp 138−140 °C; 1H NMR
(400 MHz, CDCl3) δ 8.65 (s, 1H), 7.93 (s, 1H), 7.34−7.15 (m, 9H),
7.05 (d, J = 7.2 Hz, 1H), 5.45 (s, 2H), 4.12 (s, 2H), 2.34 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 148.1, 141.2, 140.3, 138.9, 138.1, 135.5,
134.9, 129.9, 129.0, 128.3, 127.5, 127.1, 126.1, 123.2, 107.6, 47.7, 35.5,
21.4; HRMS calcd for C22H20N5 [M + H+] 354.1713, found 354.1705;
IR (KBr) νmax 3077, 3029, 2908, 1643, 1378, 699 cm−1.
7-Methyl-3-(4-methylbenzyl)-3H-imidazo[2,1-i]purine (2f). Yellow
solid (66.5 mg, 80%): mp 193−195 °C; 1H NMR (400 MHz, CDCl3)
δ 8.71 (s, 1H), 7.91 (s, 1H), 7.41 (s, 1H), 7.16 (dd, J = 14.4, 8.0 Hz,
4H), 5.40 (s, 2H), 2.49 (s, 3H), 2.32 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 143.6, 141.0, 140.2, 139.0, 138.1, 134.5, 132.4, 129.5, 127.5,
123.0, 107.0, 47.4, 21.0, 14.2; HRMS calcd for C16H16N5 [M + H+]
278.1400, found 278.1402; IR (KBr) νmax 3093, 2944, 2916, 1639, 746
cm−1.
3-(2-Chlorobenzyl)-7-methyl-3H-imidazo[2,1-i]purine (2g).
Brown solid (67.7 mg, 76%): mp 161−163 °C; 1H NMR (400
MHz, CDCl3) δ 8.59 (s, 1H), 8.01 (s, 1H), 7.42 (d, J = 8.4 Hz, 1H),
7.36 (s, 1H), 7.29−7.13 (m, 3H), 5.60 (s, 2H), 2.57 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 140.5, 138.8, 134.7, 133.4, 133.3, 133.2, 131.2,
129.9, 129.8, 129.6, 127.3, 123.5, 119.1, 45.4, 9.3; HRMS calcd for
C15H13ClN5 [M + H+] 298.0854, found 298.0850; IR (KBr) νmax 3073,
2991, 2921, 1640, 1370, 748 cm−1.
3-((3aS,4S,6S,6aS)-2,2-Dimethyl-6-((trityloxy)methyl)-
tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-7-methyl-3H-imidazo[2,1-i]-
purine (2h). Brown oil (153.3 mg, 87%): 1H NMR (400 MHz,
CDCl3) δ 8.26 (s, 1H), 8.01 (s, 1H), 7.38 (s, 1H), 7.34 (s, 3H), 7.32
(s, 3H), 7.17 (s, 1H), 7.15 (s, 3H), 7.13 (s, 2H), 7.11 (s, 1H), 7.09 (s,
1H), 7.07 (s, 1H), 6.20 (d, J = 2.4 Hz, 3H), 5.38 (dd, J = 6.0, 2.0 Hz,
1H), 4.98 (q, J = 3.2 Hz, 1H), 4.56−4.53 (m, 1H), 3.36−3.27 (m,
1H), 2.53 (s, 3H), 2.03 (s, 1H), 1.63 (s, 3H), 1.38 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 143.3, 137.3, 133.0, 131.3, 128.5, 127.6, 126.9,
114.2, 91.3, 86.7, 86.3, 84.4, 81.9, 77.3, 76.9, 76.6, 63.9, 27.1, 25.4, 9.2;
HRMS calcd for C35H34N5O4 [M + H+] 588.2605, found 588.2603; IR
(KBr) νmax 3056, 3032, 2987, 2933, 1641, 1367, 1212, 1077 cm−1.
3-Benzyl-7-(3,5-dimethylbenzyl)-3H-imidazo[2,1-i]purine (2l).
1
Brown oil (75.7 mg, 68.7%): H NMR (400 MHz, CDCl3) δ 8.48
(s, 1H), 7.95 (s, 1H), 7.45 (s, 1H), 7.34−7.31 (m, 3H), 7.27−7.25 (m,
2H), 7.25 (s, 1H), 6.88 (s, 1H), 6.82 (s, 2H), 5.43 (s, 2H), 4.25 (s,
2H), 2.25 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 140.3, 138.5,
136.0, 135.4, 133.9, 132.2, 129.0, 128.8, 128.4, 127.5, 126.0, 123.6,
122.1, 47.7, 30.3, 21.2; HRMS calcd for C23H22N5 [M + H+] 368.1870,
found 368.1869; IR (KBr) νmax 3125, 3101, 3021, 1641, 1372, 783
cm−1.
3-Benzyl-7-(3,5-dimethylbenzylidene)-7,8-dihydro-3H-imidazo-
[2,1-i]purine (3l). Yellow solid (11.3 mg, 10.3%): mp 152−154 °C; 1H
NMR (400 MHz, CDCl3) δ 8.64 (s, 1H), 7.92 (s, 1H), 7.34−7.30 (m,
3H), 7.27 (d, J = 2.4 Hz, 1H), 7.25 (s, 1H), 7.22 (s, 1H), 6.98 (s, 1H),
6.87 (s, 1H), 5.44 (s, 2H), 4.11 (s, 2H), 2.29 (s, 6H); 13C NMR (100
MHz, CDCl3) δ 148.2, 141.2, 140.3, 139.1, 138.9, 137.9, 135.5, 134.8,
129.0, 128.4, 128.0, 127.5, 126.9, 123.3, 107.5, 47.7, 35.4, 21.2; HRMS
calcd for C23H22N5 [M + H+] 368.1870, found 368.1866; IR (KBr)
νmax 3125, 3082, 3015, 1636, 1375, 779, 723 cm−1.
3-Benzyl-7-(2-methoxybenzyl)-3H-imidazo[2,1-i]purine (2m). Yel-
1
low oil (81.0 mg, 73.1%): H NMR (400 MHz, CDCl3) δ 8.61 (s,
3668
dx.doi.org/10.1021/jo5001687 | J. Org. Chem. 2014, 79, 3665−3670

The Journal of Organic Chemistry
Note
1H), 7.92 (s, 1H), 7.43 (s, 1H), 7.30 (s, 3H), 7.25−7.19 (m, 3H), 7.00
(d, J = 7.2 Hz, 1H), 6.84 (t, J = 7.6 Hz, 1H), 5.43 (s, 2H), 4.29 (s,
2H), 3.88 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 156.9, 140.3,
138.9, 135.5, 134.2, 132.0, 129.6, 129.0, 128.4, 127.5, 124.7, 123.5,
122.4, 120.9, 110.6, 55.5, 47.7, 23.8; HRMS calcd for C22H20N5O [M
+ H+] 370.1662, found 370.1663; IR (KBr) νmax 3083, 3030, 2931,
1637, 1374, 1247, 808 cm−1.
1H), 5.44 (s, 2H), 4.30 (s, 2H); 13C NMR (100 MHz, CDCl3) δ
135.4, 134.7, 133.5, 133.1, 129.6, 129.2, 129.0, 128.4, 127.6, 47.8, 30.9;
HRMS calcd for C21H17ClN5 [M + H+] 374.1167, found 374.1164; IR
(KBr) νmax 3136, 3066, 3030, 1638, 1371, 725 cm−1.
3-Benzyl-7-(4-chlorobenzylidene)-7,8-dihydro-3H-imidazo[2,1-i]-
purine (3q). Light yellow solid (54.2 mg, 48.4%): mp 205−207 °C; 1H
NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 7.85 (s, 1H), 7.26−7.17 (m,
1H), 8.19 (s, 1H), 5.37 (s, 2H), 4.06 (s, 2H); 13C NMR (100 MHz,
CDCl3) δ 147.3, 141.4, 140.4, 139.3, 137.6, 135.5, 134.9, 132.2, 130.4,
129.0, 128.6, 128.4, 127.6, 123.3, 107.6, 47.8, 34.9; HRMS calcd for
C21H17ClN5 [M + H+] 374.1167, found 374.1167; IR (KBr) νmax 3136
3077, 2934, 1634, 1371, 692 cm−1.
3-Benzyl-7-(2-methoxybenzylidene)-7,8-dihydro-3H-imidazo[2,1-
1
i]purine (3m). Green oil (13.2 mg, 11.9%): H NMR (400 MHz,
CDCl3) δ 8.62 (s, 1H), 7.91 (s, 1H), 7.31 (s, 4H), 7.26 (s, 3H), 7.18
(s, 1H), 6.90 (t, J = 8.2 Hz, 2H), 5.43 (s, 2H), 4.20 (s, 2H), 3.82 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 157.3, 147.7, 141.0, 140.3,
139.1, 135.5, 134.8, 130.8, 129.0, 128.4, 127.8, 127.6, 127.5, 123.3,
120.6, 110.5, 107.5, 55.4, 47.7, 29.6; HRMS calcd for C22H20N5O [M
+ H+] 370.1662, found 370.1660; IR (KBr) νmax 3079, 3017, 2832,
1641, 1371, 1244, 723 cm−1.
3-Benzyl-7-(4-fluorobenzyl)-3H-imidazo[2,1-i]purine (2r). Brown
1
oil (34.6 mg, 32.3%): H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H),
7.89 (s, 1H), 7.25−7.20 (m, 7H), 7.34−7.27 (m, 7H), 7.09 (s, 1H),
7.07 (s, 1H), 5.36 (s, 2H), 4.23 (s, 2H); 13C NMR (100 MHz, CDCl3)
δ 135.4, 134.7, 133.1, 129.6, 129.2, 129.0, 128.4, 127.6, 47.8, 29.9;
HRMS calcd for C21H17FN5 [M + H+] 358.1463, found 358.1456; IR
(KBr) νmax 3084, 2937, 2839, 1638, 1375, 1240, 727 cm−1.
3-Benzyl-7-(4-methoxybenzyl)-3H-imidazo[2,1-i]purine (2n). Yel-
1
low oil (82.8 mg, 74.8%): H NMR (400 MHz, CDCl3) δ 8.45 (s,
1H), 7.94 (s, 1H), 7.44 (s, 1H) 7.31−7.27 (m, 3H), 7.20−7.23 (m,
2H), 7.11 (d, J = 7.6 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 5.41 (s, 2H),
4.24 (s, 2H), 3.76 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.6,
135.5, 133.8, 129.2, 128.9, 128.3, 127.5, 114.3, 55.2, 47.7, 29.6; HRMS
calcd for C22H20N5O [M + H+] 370.1662, found 370.1662; IR (KBr)
νmax 3079, 2977, 2927, 1639, 1246, 703, 525 cm−1.
3-Benzyl-7-(4-fluorobenzylidene)-7,8-dihydro-3H-imidazo[2,1-i]-
1
purine (3r). Brown solid (45.8 mg, 42.8%): mp 144−146 °C; H
NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 7.92 (s, 1H), 7.31−7.24 (m,
8H), 6.98 (t, J = 8.4 Hz, 2H), 5.44 (s, 2H), 4.14 (s, 2H); 13C NMR
(100 MHz, CDCl3) δ 162.8, 160.4, 147.7, 141.4, 140.4, 139.2, 135.5,
134.9, 134.8, 134.8, 130.5, 130.5, 129.0, 128.4, 127.5, 123.3, 115.3,
115.1, 107.6, 47.7, 34.7; HRMS calcd for C21H16FN5Na [M + Na+]
380.1282, found 380.1273; IR (KBr) νmax 3074, 3014, 2917, 2865,
1638, 1375, 695 cm−1.
3-Benzyl-7-(4-methoxybenzylidene)-7,8-dihydro-3H-imidazo[2,1-
1
i]purine (3n). Yellow solid (11.3 mg, 10.2%): mp 175−177 °C; H
NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 7.93 (s, 1H), 7.34−7.25 (m,
7H), 7.19 (s, 1H), 6.86 (d, J = 8.4 Hz, 2H), 5.45 (s, 2H), 4.13 (s, 2H),
3.78 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.1, 135.5, 134.9,
131.1, 130.1, 129.0, 128.3, 127.5, 113.8, 55.2, 47.7, 34.7; HRMS calcd
for C22H20N5O [M + H+] 370.1662, found 370.1663; IR (KBr) νmax
3082, 2984, 2918, 1645, 1238, 725 cm−1.
3-Benzyl-7-(thiophen-2-ylmethyl)-3H-imidazo[2,1-i]purine (2s).
1
Brown oil (35.9 mg, 34.7%): H NMR (400 MHz, CDCl3) δ 8.68
(s, 1H), 7.93 (s, 1H), 7.37−7.33 (m, 5H), 7.26 (s, 1H), 7.18 (d, J = 4.8
Hz, 2H), 7.00 (s, 1H), 6.96 (s, 1H), 5.45 (s, 2H), 4.40 (s, 2H); 13C
NMR (100 MHz, CDCl3) δ 147.2, 141.0, 140.4, 139.2, 135.4, 134.9,
129.0, 128.4, 127.5, 126.8, 125.9, 124.0, 107.6, 47.8, 29.7; HRMS calcd
for C19H15N5NaS [M + Na+] 368.0940, found 368.0947; IR (KBr)
νmax 3071, 2923, 1640, 1373, 1350, 688, 647 cm−1.
3-Benzyl-7-(thiophen-2-ylmethylene)-7,8-dihydro-3H-imidazo-
[2,1-i]purine (3s). Brown solid (43.8 mg, 42.4%): mp 165−167 °C; 1H
NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 7.94 (s, 1H), 7.38 (s, 1H),
7.34 (s, 3H), 7.27 (s, 2H), 7.19 (d, J = 4.0 Hz, 1H), 7.00 (s, 1H), 6.97
(s, 1H), 5.46 (s, 2H), 4.41 (s, 2H); 13C NMR (100 MHz, CDCl3) δ
147.2, 141.1, 140.4, 135.4, 135.0, 129.0, 128.4, 127.6, 126.9, 125.9,
124.1, 123.3, 107.6, 47.8, 29.8; HRMS calcd for C19H15N5NaS [M +
Na+] 368.0940, found 368.0944; IR (KBr) νmax 3071, 2924, 1640,
1373, 1345, 725, 647 cm−1.
3-Benzyl-7-(4-ethoxybenzyl)-3H-imidazo[2,1-i]purine (2o). Brown
oil (93.1 mg, 81%): 1H NMR (400 MHz, CDCl3) δ 8.46 (s, 1H), 7.93
(s, 1H), 7.45 (s, 1H), 7.32 (s, 3H), 7.25 (s, 2H), 7.11 (d, J = 4.4 Hz,
2H), 6.82 (s, J = 8.0 Hz, 2H), 5.43 (s, 2H), 4.26 (s, 2H), 3.99 (q, J =
7.2 Hz, 2H), 1.39 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
158.1, 141.8, 140.3, 138.9, 135.5, 133.8, 132.3, 129.2, 129.0, 128.4,
127.9, 127.6, 123.7, 122.4, 114.9, 63.5, 47.8, 29.7, 14.8; HRMS calcd
for C23H21N5NaO [M + Na+] 406.1638, found 406.1647; IR (KBr)
νmax 3098, 3010, 2983, 1641, 1375, 1241, 705, 519 cm−1.
3-Benzyl-7-(4-ethoxybenzylidene)-7,8-dihydro-3H-imidazo[2,1-i]-
1
purine (3o). Yellow solid (8.1 mg, 7%): mp 146−148 °C; H NMR
(400 MHz, CDCl3) δ 8.63 (s, 1H), 7.91 (s, 1H), 7.33−7.30 (m, 3H),
7.28 (s, 2H), 7.26−7.24 (m, 2H), 7.12 (s, 1H), 6.84 (d, J = 8.8 Hz,
2H), 5.44 (s, 2H), 4.12 (s, 2H), 4.01 (q, J = 7.20 Hz, 2H), 1.40 (t, J =
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 157.6, 148.6, 141.3,
140.3, 139.2, 135.5, 134.9, 131.0, 130.1, 129.0, 128.4, 127.5, 123.3,
114.5, 107.5, 63.4, 47.7, 34.7, 14.9; HRMS calcd for C23H21N5NaO [M
+ Na+] 406.1638, found 406.1641; IR (KBr) νmax 3095, 3013, 2981,
1647, 1371, 1238, 723 cm−1.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra of compounds 2a−2s and
3i−3s. This material is available free of charge via the Internet
at http://pubs.acs.org.
3-Benzyl-7-(3-chlorobenzyl)-3H-imidazo[2,1-i]purine (2p). Brown
1
oil (42.6 mg, 38.1%): H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H),
AUTHOR INFORMATION
Corresponding Authors
*Fax: (+86) 373-3329276. E-mail: quguir@sina.com.
*E-mail: guohm518@hotmail.com.
7.97 (s, 1H), 7.50 (s, 1H), 7.35−7.31 (m, 3H), 7.24−7.23 (m, 5H),
7.22 (s, 1H), 7.11−7.09 (m, 1H), 5.45 (s, 2H), 4.32 (s, 2H); 13C NMR
(100 MHz, CDCl3) δ 140.5, 139.0, 138.2, 135.3, 134.9, 133.4, 132.7,
130.2, 129.0, 128.4, 128.3, 127.5, 126.3, 123.6, 121.0, 47.8, 30.1;
HRMS calcd for C21H16ClN5Na [M + Na+] 396.0986, found
396.0981; IR (KBr) νmax 3128, 3063, 2922, 1642, 1371, 715 cm−1.
3-Benzyl-7-(3-chlorobenzylidene)-7,8-dihydro-3H-imidazo[2,1-i]-
purine (3p). Light yellow solid (48.1 mg, 42.9%): mp 210−213 °C; 1H
NMR (400 MHz, (CD3)2SO) δ 9.27 (s, 1H), 8.53 (s, 1H), δ 7.90 (s,
1H), 7.42 (s, 1H), 7.35−7.28 (m, 8H), 5.55 (s, 2H), 4.14 (s, 2H); 13C
NMR (100 MHz, CDCl3) δ146.9, 141.1, 140.4, 139.2, 135.4, 134.9,
134.1, 129.7, 129.1, 129.0, 128.4, 127.5, 127.3, 126.6, 123.3, 107.7,
47.7, 35.1; HRMS calcd for C21H17ClN5 [M + H+] 374.1167, found
374.1164; IR (KBr) νmax 3063, 2925, 2854, 1641, 1376, 698 cm−1.
3-Benzyl-7-(4-chlorobenzyl)-3H-imidazo[2,1-i]purine (2q). Brown
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of China (Grant Nos. 21172059,
21272059, 21202039, and 21372066), 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
1
oil (44.3 mg, 39.6%): H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H),
7.97 (s, 1H), 7.48 (s, 1H), 7.34−7.27 (m, 7H), 7.16 (s, 1H), 7.14 (s,
3669
dx.doi.org/10.1021/jo5001687 | J. Org. Chem. 2014, 79, 3665−3670

The Journal of Organic Chemistry
Note
(8) Guo, H.-M.; Wu, S.; Niu, H.-Y.; Song, G.; Qu, G.-R. Chemical
Synthesis of Acyclic Nucleosides in Chemical Synthesis of Nucleoside
Analogues 3; Pedro, M., Ed.; John Wiley & Sons: New York, 2013; pp
103−162.
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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