Microwave-assisted regioselective synthesis of acyclic nucleosides through an alkylating reaction with 2-oxa-1,4-butanediol diacetate

Article abstract of DOI:10.1139/V06-061

An efficient and green procedure for the synthesis of purine acyclic nucleosides through microwave-assisted, alkylation of various purine nucleobases with 2-oxa-1,4-butanediol diacetate in the absence of solvent and catalyst is described. The advantages of using this method include its environmental friendliness, simple manipulation, short reaction time, high regioselectivity, and good yields.

Full text of DOI:10.1139/V06-061

819
Microwave-assisted regioselective synthesis of
acyclic nucleosides through an alkylating reaction
with 2-oxa-1,4-butanediol diacetate
Guirong Qu, Suhui Han, Zhiguang Zhang, Mingwei Geng, and Feng Xue
Abstract: An efficient and green procedure for the synthesis of purine acyclic nucleosides through microwave-assisted
alkylation of various purine nucleobases with 2-oxa-1,4-butanediol diacetate in the absence of solvent and catalyst is
described. The advantages of using this method include its environmental friendliness, simple manipulation, short reac-
tion time, high regioselectivity, and good yields.
Key words: acyclic nucleosides, microwave irradiation, regioselectivity, alkylation, 2-oxa-1,4-butanediol diacetate.
Résumé : On a mis au point une méthode efficace et verte pour la synthèse de nucléosides acyclique de l’acide qui
fait appel à une alkylation à l’aide de micro-onde de nucléobases purines avec le diacétate du 2-oxa-1,4-butanediol en
absence de solvant et de catalyseur. Les avantages de cette méthode reposent sur son caractère écologique, sa facilité
de manipulation, sa faible durée de réaction, sur sa grande régiosélectivité et sur ses bons rendements.
Mots clés : nucléosides acycliques, irradiation micro-onde, régiosélectivité, alkylation, diacétate du 2-oxa-1,4-
butanediol.
[Traduit par la Rédaction] Qu et al. 824
Introduction
methyl) derivatives of purines with moderate yields. Unfor-
tunately, the obtained acyclic nucleosides often were N9/N7
isomeric mixtures that were difficult to separate (4). Subse-
quent studies showed the problems resulting from the classi-
cal alkylating procedures can be overcome either by heating
the mixture of N2,N9-diacetylguanine and 2-oxa-1,4-
butanediol diacetate at 105 °C for 80 h to generate the de-
sired N2-acetyl-9-(2-acetoxyethoxymethyl)guanine in high
yield (5). However, these methods still have some draw-
backs, notably requiring the use of an oil bath that can main-
tain the reaction mixture at 105 °C for 80 h, thus making
these methods unsuitable for scale up in an environmentally
benign and economical way.
Microwave irradiation as a nonconventional energy source
has been a very popular and useful technique in organic
chemistry (6). The combination of microwave irradiation
and solvent-free reaction conditions leads to significantly re-
duced reaction time, enhanced conversions, and sometimes,
higher selectivity, with several advantages for the eco-
friendly approach, termed green chemistry. The synthesis of
acyclic nucleosides accelerated by this technique is scarce
(7). In line with our research program of using microwave
irradiation to synthesize a series of nucleoside compounds
(8), we wish to report here a facile and efficient procedure
for the synthesis of 9-(2-acetoxyethoxymethyl) derivatives of
purines through a solvent-free alkylating reaction of purine
In the past two decades, considerable efforts have been
invested to develop an efficient treatment against human im-
munodeficiency virus (HIV) infection. The use of acyclic
nucleosides as therapeutic agents, such as acyclovir (1),
ganciclovir (2), and penciclovir (3) (Fig. 1), leads to promis-
ing results in the treatment of patients with devastating in-
fections by viruses such as varicella zoster virus (VZV),
human cytomegalovirus (HCMV), Epstein–Barr virus
(EBV), and herpes viruses (1). While versatile methods for
the synthesis of acyclic nucleosides have been developed
(2), many of them suffer from harsh reaction conditions, the
use of expensive alkylating reagents and catalysts, long reac-
tion time, and low selectivity and yields. Thus, simple and
efficient protocols for the synthesis of acyclic nucleosides
with excellent bioactivities are still in demand.
As one of the most frequently used pathways to prepare
purine acyclic nucleosides, the alkylating reaction involves
the condensation of purine nucleobases with a haloalkyl
ether, trimethylsilyalkyl ether, or polyfunctional open-chain
riboside analogues having a reactive α-methylene group (3).
This classical process is usually carried out by freezing a
DMF solution of reactants at temperatures ranging from –78
to –50 °C in the presence of strong bases or Lewis acids to
produce corresponding functionalized 9-(2-acetoxyethoxy-
Received 31 October 2005. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on 19 May 2006.
G. Qu,1 S. Han, Z. Zhang, M. Geng, and F. Xue. College of Chemistry and Environmental Science, Key Laboratory of
Environmental Science and Engineering for Colleges and Universities of Henan Province, Henan Normal University, Xinxiang
453007, Henan, P.R. China.
1Corresponding author (e-mail: quguir@163.com).
Can. J. Chem. 84: 819–824 (2006)
doi:10.1139/V06-061
© 2006 NRC Canada

820
Can. J. Chem. Vol. 84, 2006
Fig. 1. Structures of acyclovir (1), ganciclovir (2), and penciclovir (3).
O
N
O
N
O
N
N
N
NH
NH
NH2
N
NH
HO
HO
HO
HO
N
NH2
O
HO
N
N
NH2
O
2
3
1
Scheme 1. Microwave-assisted regioselective synthesis of purine acyclic nucleosides 6a–6o.
R1
R1
N
N
N
MWI, 4-8 min
Al2O3 bath
N
OAc
+
AcO
O
N
R3
AcO
N
N
R2
N
R2
O
4a-4o
6a-6o
5
Scheme 2. Microwave-assisted synthesis of 6a under solvent-free conditions.
Cl
N
R1
N
N
MWI, 4 min
Al2O3 bath
N
OAc
+
AcO
O
N
AcO
N
N
N
R2
O
H
4a
6a
5
Table 1. Alkylating reaction of 6-chloropurine (4a) and 2-oxa-1,4-butanediol diacetate (5) in dif-
ferent conditions under microwave irradiation.
Equivalents
of 5
Microwave
power (W)
Reaction
time (min)
Yield
(%)a
Entry
Catalyst
1
10
3
3
3
3
None
None
None
None
PTSA
NP–ZnBr2
400
400
400
400
400
400
10
5
5
4
8
34
31
0
93
36
12
2b
3c
4d
5
6
3
8
7
8
9
10
11e
3
3
3
3
3
K10 mont.
None
None
None
None
400
400
500
600
400
9
6
4
4
4
58
85
78
65
52
aIsolated yields for 6a purified by silica gel column chromatography (CHCl3–CH3OH, 95:5 v/v).
bNeutral alumina was used as the supporting agent.
cSilica gel was used as the supporting agent.
dNeutral alumina as the bath and silica gel as the supporting material were used. This condition is applied for
entries 4–10.
eSilica gel as the bath and neutral alumina as the supporting material were used.
4a on TLC. After purification by column chromatography,
nucleobases with 2-oxa-1,4-butanediol diacetate in a neutral
alumina bath using silica gel as the supporting material un-
der microwave irradiation (Scheme 1).
the compound with the higher Rf was proved to be the N9
isomer by HMBC with 34% isolated yield, and the one with
the lower Rf was the N7 isomer with a similar yield, which
showed the regioselectivity was very low (Table 1, entry 1).
To reduce the ratio of the N7 isomer, we shortened the
equivalents of 5 to 3 and added an appropriate amount of
neutral alumina as the supporting material to overcome the
possible agglomeration because of the decrease of the fluid
5. After being crushed vigorously with neutral alumina, the
mixture was irradiated in a small beaker at 400 W for 5 min.
To our delight, the desired N9 isomer was predominant for
the part facing the irradiation source, which was almost
Results and discussion
We set out to optimize the alkylating reaction conditions
under microwave irradiation, using 6-chloropurine (Scheme 2,
4a) and 2-oxa-1,4-butanediol diacetate (5) as the starting
materials.
Firstly, the mixture of 4a and 5 (10 equiv.) in a 25 mL
round-bottomed flask was irradiated directly at 400 W for
10 min, two obvious new spots both showing higher Rf than
© 2006 NRC Canada

Qu et al.
821
Table 2. Regioselective synthesis of 9-(2-acetoxyethoxymethyl) derivatives of purines through micro-
wave-assisted alkylation of various purine nucleobases with 2-oxa-1,4-butanediol diacetate (5).
Microwave
power (W)
Reaction
time (min)
Yield
(%)a
R1
R2
R3
Entry
Product
1
2
3
Cl
Cl
H
Cl
H
H
H
H
400
300
600
4
6
4
6a
6b
6c
93
91
95
NHCH2C6H5
4
5
6
OH
OH
NHC6H11
AcNH
H
H
Ac
H
H
500
500
500
5
5
8
6d
6e
6f
48
53
82
7
8
NHC6H5
H
H
H
H
H
H
H
H
H
H
500
550
500
550
550
500
500
500
550
8
8
8
8
8
8
8
8
8
6g
6h
6i
85
80
80
79
81
83
78
76
62
NHC6H4CH3-p
NHC6H4OCH3-p
NHC6H4OC2H5-p
NHC6H11
H
9
H
10
11
12
13
14
15
H
6j
Cl
Cl
Cl
Cl
NH2
6k
6l
NHC6H5
NHC6H4CH3-p
NHC6H4OCH3-p
NHC6H4CH3-p
6m
6n
6o
aIsolated yields for 6a–6o purified by silica gel column chromatography.
molted to yellow; the part opposite of the irradiation source
remained white and no obvious reaction took place as indi-
cated by TLC. The integrated yield of this method is low
(Table 1, entry 2). Under the same conditions, no new spot
was observed using silica gel instead of neutral alumina as
the supporting material (Table 1, entry 3). Considering the
different absorption capacities of neutral alumina and silica
gel to microwave, we chose neutral alumina as the bath and
silica gel as the supporting material. Fortunately, the ex-
pected product 6a was obtained with high yield when the
bath system was irradiated at 400 W for 4 min (Table 1, en-
try 4). Further studies showed that the yields could not be
improved when p-toluenesulfonic acid (PTSA), ZnBr2-doped
natural phosphate (NP–ZnBr2) (9), or K10 montmorillonite
(K10 mont.) were used as catalysts (Table 1, entries 5–7), or
when the microwave irradiation time and power were in-
creased (Table 1, entries 8–10). So we chose 400 W and
4 min as irradiation conditions and no catalyst was used.
As for the possible mechanism of this reaction, we believe
that the microwave energy was accumulated quickly by the
alumina bath and dramatically accelerated the molecule ac-
tivity of the mixture in a very short time and made the reac-
tion easily occur at position 9 and not 7 because of the
electronic origin (10–12).
Table 3. A comparative synthesis of compounds 6a and 6b using
the conventional protocol of Robins and Hatfield (2b) vs. the
solvent-free, microwave-assisted method.
Product
Time (h)a
Yield (%)a
Time (min)b
Yield (%)b
6a
6b
6
6
81
87
4
4
93
91
aConventional protocol of Robins and Hatfield (2b).
bSolvent-free, microwave-assisted method.
as the supporting agent also eases the work-up manipulation,
which can permit direct purification by silica gel column
chromatography.
To demonstrate the advantage of our method, we synthe-
sized compounds 6a and 6b following the conventional pro-
tocol of Robins and Hatfield (2b) and compared the results
with the microwave irradiation method (Table 3). As Table 3
indicates, an acceleration of the reaction rate on the order of
a 90-fold increase is observed when the microwave was
used. Higher yields of 6a and 6b were reached at 4–6 min
with microwave heating than those obtained at 6 h using the
classical method.
Based on the above results, this process was then ex-
tended to other purine substrates to investigate its scope and
generality (Table 2). It can be seen that under microwave ir-
radiation, a wide range of purine nucleobases can be
alkylated easily with 5 to give 9-(2-acetoxyethoxymethyl)
purine analogs in a short time and with very high yields
(Table 2, entries 1–3). When 6-substituted aminopurines (4f–
4n) were used as the substrates, the desired N9 products (6f–
6n) can be obtained with good yields (Table 2, entries 6–14).
In the structures of 4f–4n, the unmatched electrons on the
nitrogen atom can spread effectively to the aromatic ring,
which decreased the possibility of an electron density in-
crease at position 7. In addition, the use of silica gel acting
In conclusion, the solvent-free, microwave-assisted alkyl-
ating reaction was proved to be a useful and facile protocol
to synthesize a series of 9-(2-acetoxyethoxymethyl) deriva-
tives of purines with high regioselectivity. The system of
alumina as bath and silica gel as supporting agent was found
to be efficient for the quick absorption of microwave energy
and for the dramatic and homogeneous acceleration of the
reactions. The simple experimental and product isolation
procedures are expected to contribute to the development of
greener and waste-free chemical processes for the prepara-
tion of other acyclic nucleosides. Further studies to develop
other new uses for microwave irradiation in the synthesis of
nucleoside compounds are now in progress in our laboratory.
© 2006 NRC Canada

822
Can. J. Chem. Vol. 84, 2006
1.12–1.90 (m, 10H, H cyclohexyl), 1.94 (s, 3H, COCH3),
3.71 (t, 2H, J = 4.8 Hz, OCH2CH2OAc), 4.08 (t, 2H, J =
4.8 Hz, OCH2CH2OAc), 4.13 (br, 1H, H cyclohexyl), 5.57
(s, 2H, NCH2O), 7.56 (d, 1H, J = 8.0 Hz, NH), 8.23 (s, 1H,
H-2), 8.27 (s, 1H, H-8). 13C NMR (100 MHz, DMSO-d6) δ:
20.95 (COCH3), 25.43, 25.68, 32.78, 49.12 (C cyclohexyl),
63.21 (OCH2CH2OAc), 67.34 (OCH2CH2OAc), 72.42
(NCH2O), 119.09 (5-C), 141.18 (8-C), 149.56 (4-C), 153.37
(2-C), 154.28 (6-C), 170.64 (COCH3). MS (ESI) m/z + Na+ –
1: 355.8, 333.8, 247.9, 229.9, 217.8, 165.9, 147.7. Anal.
calcd. for C16H23N5O3 (%): C 57.64, H 6.95, N 21.01;
found: C 57.53, H 6.99, N 21.12.
Experimental
Melting points were determined with an XRC-1 micro
melting point apparatus and are uncorrected. 1H and 13C
NMR spectra were recorded in CDCl3 and DMSO-d6 solu-
tions on a Bruker DPX-400 spectrometer (at 400 and
100 MHz, respectively) using TMS as internal standard.
Chemical shifts (δ) are expressed in ppm and coupling con-
stants (J) are given in Hz. IR spectra were recorded for KBr
tablets on a Bruker Vector 22 spectrometer with absorptions
expressed in cm–1. Mass spectra (ESI) were recorded on an
Agilent 1100 (LC–MSD-Tarp-SL) mass spectrometer. Ele-
mental analyses were performed on an EA-1110 (CE Instru-
ments) instrument.
The starting substrates 4a–4e and 5 were achieved from
Xinxiang Tuoxin Biochemical Technology and Science Co.
Ltd, P.R. China. 4f–4o were synthesized by the amination of
4a, 4b, and 2-amino-6-chloropurine with the corresponding
amines (our unpublished work). All reagents were reagent
grade and used without any further purification. The prog-
ress of reaction was followed by TLC analysis using silica
gel plates (Merck, silica gel 60F254). Column chromatogra-
phy was performed on silica gel (Merck, 200–300 mesh).
All the reactions were carried out in a SANYO EM-202MSI
microwave oven.
9-[(2-Acetoxyethoxy)methyl]-6-phenylaminopurine (6g)
Melting point 84 to 85 °C. IR v (cm–1): 3354, 1727, 1627,
1
1582, 1500, 1050, 759. H NMR (400 MHz, DMSO-d6) δ:
1.95 (s, 3H, CH3CO), 3.76 (t, J = 4.8 Hz, 2H, AcOCH2CH2),
4.10 (t, J = 4.8 Hz, 2H, AcOCH2CH2), 5.66 (s, 2H,
NCH2O), 7.05 (t, 1H, J = 7.2 Hz, HAr), 7.34 (t, 2H, J =
8.0 Hz, HAr), 7.96 (d, 2H, J = 8.0 Hz, HAr), 8.45 (s, 1H, H-
2), 8.48(s, 1H, H-8). 13C NMR (100 MHz, DMSO-d6) δ:
20.97 (COCH3), 63.21 (AcOCH2CH2O), 67.49 (AcOCH2CH2O),
72.65 (NCH2O), 120.04 (5-C), 121.31, 123.10, 128.82,
140.04 (CAr), 142.52 (8-C), 150.38 (6-C), 152.54 (4-C),
152.85 (2-C), 170.65 (COCH3). MS (ESI) m/z + Na+ – 1:
349.8, 327.6. Anal. calcd. for C16H17N5O3 (%): C 58.71, H
5.23, N 21.39; found: C 58.62, H 5.28, N 21.47.
General procedure for the synthesis of 9-[(2-
acetoxyethoxy)methyl]-6-chloropurine (6a)
In a mortar, a mixture of 6-chloropurine 4a (0.308 g,
2 mmol) and 2-oxa-1,4-butanediol diacetate (5) (0.94 mL,
6 mmol) was crushed vigorously to give a homogeneous
mass, an appropriate amount of silica gel (Merck, 200–300
mesh) was added as supporting agent and mixed carefully
with a small spatula to give a fluent mixture. Subsequently,
the mixture was transferred to a small beaker (5 mL), which
was placed in an alumina bath (60 g neutral alumina (>70
mesh) was placed in a big beaker (100 mL)). The system
was irradiated at 400 W for 4 min at several time intervals.
At each irradiation time interval (1 min), the microwave was
stopped and then the reaction mixture was stirred with a
small spatula to homogenize the reaction mixture. After the
reaction was completed (monitored by TLC), the reaction
mixture was purified directly by silica gel column chroma-
tography (CHCl3–CH3OH, 95:5 v/v) to give 6a (0.503 g,
93% yield). Compounds 6b–6o were synthesized from the
corresponding starting materials 4b–4o under similar proce-
dure. The spectra data of 6a–6e were identified by using the
available literature (2b, 3d, 13, 14). The melting point of 6e
was not available and compounds 6f–6o were unknown. All
9-[(2-Acetoxyethoxy)methyl]-6-(p-tolylamino)purine (6h)
Melting point 69–71 °C. IR v (cm–1): 3321, 1726, 1642,
1585, 1237, 1054, 766. H NMR (400 MHz, DMSO-d6) δ:
1
1.94 (s, 3H, CH3CO), 2.28 (s, 3H, CH3CAr), 3.75 (t, J =
4.8 Hz, 2H, AcOCH2CH2), 4.09 (t, J = 4.8 Hz, 2H,
AcOCH2CH2), 5.65 (s, 2H, NCH2O), 7.14 (d, 2H, J =
8.4 Hz, HAr), 7.81 (d, 2H, J = 8.4 Hz, HAr), 8.42 (s, 1H, H-
2), 8.45 (s, 1H, H-8), 9.82 (s, 1H, NH). 13C NMR
(100 MHz, DMSO-d6) δ: 20.96 (COCH3), 26.68 (CH3CAr),
63.21 (AcOCH2CH2O), 67.47 (AcOCH2CH2O), 72.63
(NCH2O), 119.93 (5-C), 121.43, 129.23, 132.08, 137.45
(CAr), 142.34 (8-C), 150.26 (6-C), 152.60 (4-C), 152.90 (2-
C), 170.65 (COCH3). MS (ESI) m/z + Na+ – 1: 363.8, 300.0,
281.8, 251.8, 125.3. Anal. calcd. for C17H19N5O3 (%): C
59.81, H 5.61, N 20.52; found: C 59.64, H 5.67, N 20.65.
9-[(2-Acetoxyethoxy)methyl]-6-(p-methoxyphenyl-
amino)purine (6i)
1
Colorless oil. H NMR (400 MHz, DMSO-d6) δ: 1.95 (s,
1
new compounds were fully characterized by IR, H NMR,
3H, CH3CO), 3.75 (s, 3H, CH3O), 3.75 (t, J = 4.8 Hz, 2H,
AcOCH2CH2), 4.10 (t, J = 4.8 Hz, 2H, AcOCH2CH2), 5.64
(s, 2H, NCH2O), 6.93 (d, 2H, J = 9.2 Hz, HAr), 7.80 (d, 2H,
J = 9.2 Hz, HAr), 8.38(s, 1H, H-2), 8.43(s, 1H, H-8), 9.77 (s,
1H, NH). 13C NMR (100 MHz, DMSO-d6) δ: 20.94
(COCH3), 55.62 (CH3O), 63.21 (AcOCH2CH2O), 67.46
(AcOCH2CH2O), 72.61 (NCH2O), 119.76 (5-C), 114.04,
123.21, 132.95 (CAr), 142.16 (8-C), 150.16 (6-C), 152.96 (4-
C), 155.62 (2-C), 170.66 (COCH3). MS (ESI) m/z + Na+ – 1:
377.0, 357.8, 241.7, 226.7, 198.7, 113.6. Anal. calcd. for
C17H19N5O4 (%): C 57.14, H 5.36, N 19.60; found: C 57.04,
H 5.42, N 19.68.
13C NMR, MS, and elemental analysis.
9-[(2-Acetoxyethoxy)methyl]hypoxanthine (6e)
1
Melting point 170–172 °C. H NMR (400 MHz, DMSO-
d6) δ: 1.94 (s, 3H, CH3CO), 3.70 (t, J = 4.4 Hz, 2H,
AcOCH2CH2), 4.07 (t, J = 4.4 Hz, 2H, AcOCH2CH2), 5.56
(s, 2H, NCH2O), 8.08 (s, 1H, H-2), 8.23 (s, 1H, H-8).
9-[(2-Acetoxyethoxy)methyl]-6-cyclohexylaminopurine (6f)
Melting point 118–120 °C. IR v (cm–1): 3218, 2935, 1744,
1
1598, 1243, 1048, 761. H NMR (400 MHz, DMSO-d6) δ:
© 2006 NRC Canada

Qu et al.
823
400.6, 242.8, 156.7, 103.0. Anal. calcd. for C17H18ClN5O3
(%): C 54.33, H 4.83, N 18.64; found: C 54.13, H 4.89, N
18.82.
9-[(2-Acetoxyethoxy)methyl]-6-(p-ethoxyphenylamino)-
purine (6j)
Melting point 117–119 °C. IR v (cm–1): 3415, 1739, 1619,
1
1512, 1232, 1043, 760. H NMR (400 MHz, DMSO-d6) δ:
9-[(2-Acetoxyethoxy)methyl]-2-chloro-6-(p-methoxy-
phenylamino)purine (6n)
1.94 (s, 3H, CH3CO), 2.28 (s, 3H, CH3CAr), 3.75 (t, J =
4.8 Hz, 2H, AcOCH2CH2), 4.09 (t, J = 4.8 Hz, 2H,
AcOCH2CH2), 5.65 (s, 2H, NCH2O), 7.14 (d, 2H, J =
8.4 Hz, HAr), 7.81 (d, 2H, J = 8.4 Hz, HAr), 8.42 (s, 1H, H-
2), 8.45 (s, 1H, H-8), 9.82 (s, 1H, NH). 13C NMR
(100 MHz, DMSO-d6) δ: 15.16 (OCH2CH3), 20.97
(COCH3), 63.21 (AcOCH2CH2O), 63.56 (OCH2CH3), 67.46
(AcOCH2CH2O), 72.60 (NCH2O), 119.75 (5-C), 114.60,
123.16, 132.87 (CAr), 142.18 (8-C), 150.15 (6-C), 152.96 (4-
C), 154.85 (2-C), 170.65 (COCH3). MS (ESI) m/z + Na+ – 1:
393.8, 371.8, 255.8, 227.8, 198.8, 158.8, 119.7. Anal. calcd.
for C18H21N5O4 (%): C 58.21, H 5.70, N 18.86; found: C
58.07, H 5.79, N 18.95.
Melting point 140–142 °C. IR v (cm–1): 3375, 1720, 1627,
1
1510, 1257, 1045. H NMR (400 MHz, DMSO-d6) δ: 1.95
(s, 3H, CH3CO), 3.76 (s, 3H, CH3O), 3.74 (t, J = 4.8 Hz,
2H, AcOCH2CH2), 4.10 (t, J = 4.8 Hz, 2H, AcOCH2CH2),
5.59 (s, 2H, NCH2O), 6.95 (d, 2H, J = 8.8 Hz, HAr), 7.69 (d,
2H, J = 8.8 Hz, HAr), 8.43 (s, 1H, H-8), 10.21 (s, 1H, NH).
13C NMR (100 MHz, DMSO-d6) δ: 20.95 (COCH3), 55.66
(CH3O), 63.19 (AcOCH2CH2O), 67.40 (AcOCH2CH2O),
72.84 (NCH2O), 118.92 (5-C), 114.18, 123.70, 131.95 (CAr),
142.66 (8-C), 151.18 (6-C), 153.10 (4-C), 156.24 (2-C),
170.64 (COCH3). MS (ESI) m/z + Na+ – 1: 413.8, 391.7.
Anal. calcd. for C17H18ClN5O4 (%): C 52.11, H 4.63, N
17.87; found: C 51.99, H 4.72, N 17.94.
9-[(2-Acetoxyethoxy)methyl]-2-chloro-6-cyclohexylamino-
purine (6k)
1
9-[(2-Acetoxyethoxy)methyl]-2-amino-6-(p-tolylamino)-
purine (6o)
Colorless oil. H NMR (400 MHz, DMSO-d6) δ: 1.11–
1.86 (m, 10H, H cyclohexyl), 1.94 (s, 3H, COCH3), 3.69 (t,
2H, J = 4.8 Hz, OCH2CH2OAc), 4.01 (br, 1H, H
cyclohexyl), 4.08 (t, 2H, J = 4.8 Hz, OCH2CH2OAc), 5.53
(s, 2H, NCH2O), 8.17 (d, 1H, J = 8.0 Hz, NH), 8.31 (s, 1H,
H-8). 13C NMR (100 MHz, DMSO-d6) δ: 20.95 (COCH3),
25.14, 25.36, 25.56, 32.46, 33.48, 49.45 (C cyclohexyl),
63.19 (OCH2CH2OAc), 67.30 (OCH2CH2OAc), 72.68 (NCH2O),
118.33 (5-C), 141.73 (8-C), 150.41 (4-C), 154.13 (2-C),
154.69 (6-C), 170.62 (COCH3). MS (ESI) m/z + Na+ – 1:
389.8, 307.8, 271.7, 212.8. Anal. calcd. for C16H22ClN5O3 (%):
C 52.24, H 6.03, N 19.04; found: C 52.10, H 6.11, N 19.12.
Melting point 76–78 °C. IR v (cm–1): 3327, 1733, 1624,
1
1598, 1513, 1243, 1051, 765. H NMR (400 MHz, DMSO-
d6) δ: 1.94 (s, 3H, CH3CO), 2.28 (s, 3H, CH3CAr), 3.76 (t,
J = 4.8 Hz, 2H, AcOCH2CH2), 4.10 (t, J = 4.8 Hz, 2H,
AcOCH2CH2), 5.56 (s, 2H, NCH2O), 7.10 (d, 2H, J =
8.4 Hz, HAr), 8.04 (d, 2H, J = 8.4 Hz, HAr), 8.31 (s, 1H, H-
8), 9.78 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6) δ:
20.91 (COCH3), 25.12 (CH3CAr), 63.21 (AcOCH2CH2O),
67.40 (AcOCH2CH2O), 72.52 (NCH2O), 116.75 (5-C),
121.06, 129.21, 131.68, 137.59 (CAr), 141.42 (8-C), 151.00
(6-C), 152.32 (4-C), 153.18 (2-C), 170.67 (COCH3). MS
(ESI) m/z + Na+ – 1: 378.8, 330.6, 204.7, 262.8. Anal. calcd.
for C17H20N6O3 (%): C 57.29, H 5.66, N 23.58; found: C
57.18, H 5.72, N 23.66.
9-[(2-Acetoxyethoxy)methyl]-2-chloro-6-phenylamino-
purine (6l)
1
Melting point 102–104 °C. H NMR (400 MHz, DMSO-
d6) δ: 1.96 (s, 3H, CH3CO), 3.74 (t, J = 4.8 Hz, 2H,
AcOCH2CH2), 4.10 (t, J = 4.8 Hz, 2H, AcOCH2CH2), 5.61
(s, 2H, NCH2O), 7.11 (t, 1H, J = 8.0 Hz, HAr), 7.38 (t, 2H,
J = 8.0 Hz, HAr), 7.84 (d, 2H, J = 8.0 Hz, HAr), 8.48 (s, 1H,
H-8). 13C NMR (100 MHz, DMSO-d6) δ: 20.98 (COCH3),
63.19 (AcOCH2CH2O), 67.44 (AcOCH2CH2O), 72.90
(NCH2O), 119.19 (5-C), 121.82, 124.05, 128.98, 139.13 (CAr),
143.03 (8-C), 151.42 (6-C), 152.96 (4-C), 153.28 (2-C),
170.64 (COCH3). MS (ESI) m/z + Na+ – 1: 383.7, 361.9,
300.0, 245.7, 145.9, 86.0. Anal. calcd. for C16H16ClN5O3
(%): C 53.12, H 4.46, N 19.36; found: C 53.02, H 4.52, N
19.43.
Acknowledgment
We thank the National Natural Science Foundation of
China (Grant No. 20372018) for financial support.
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1
Yellow oil. H NMR (400 MHz, DMSO-d6) δ: 1.96 (s,
3H, CH3CO), 2.30 (s, 3H, CH3CAr), 3.74 (t, J = 4.8 Hz, 2H,
AcOCH2CH2), 4.10 (t, J = 4.8 Hz, 2H, AcOCH2CH2), 5.60
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J = 8.4 Hz, HAr), 8.45(s, 1H, H-8), 10.26 (s, 1H, NH). 13C
NMR (100 MHz, DMSO-d6) δ: 20.94 (COCH3), 25.21
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© 2006 NRC Canada

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Can. J. Chem. Vol. 84, 2006
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