KF/Al2O3 as a highly efficient, green, heterogeneous, and reusable catalytic system for the solvent-free synthesis of carboacyclic nucleosides via Michael addition reaction

Article abstract of DOI:10.1080/00397910802369711

KF/Al2O3 acts as an efficient catalytic system for the synthesis of carboacyclic nucleosides via Michael addition of pyrimidine and purine nucleobases to α,β-unsaturated esters under solvent-free and microwave conditions. Using this method, the title comp

Full text of DOI:10.1080/00397910802369711

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KF/Al2O3 as a Highly Efficient,
Green, Heterogeneous, and
Reusable Catalytic System for
the Solvent-Free Synthesis of
Carboacyclic Nucleosides via
Michael Addition Reaction
Abdolkarim Zare a , Alireza Hasaninejad b
,
Mohammad Hassan Beyzavi c , Ahmad Reza Moosavi
Zare a , Ali Khalafi-Nezhad c , Fatemeh Asadi a
,
Leila Baramaki a , Sedigheh Jomhori-Angali a
Rokhsareh Ghaleh-Golabi a
&
a Department of Chemistry, College of Sciences,
Payame Noor University (PNU), Bushehr, Iran
b Department of Chemistry, Faculty of Sciences,
Persian Gulf University, Bushehr, Iran
c Department of Chemistry, College of Sciences,
Shiraz University, Shiraz, Iran
Published online: 15 Feb 2011.
To cite this article: Abdolkarim Zare , Alireza Hasaninejad , Mohammad Hassan
Beyzavi , Ahmad Reza Moosavi Zare , Ali Khalafi-Nezhad , Fatemeh Asadi , Leila
Baramaki , Sedigheh Jomhori-Angali & Rokhsareh Ghaleh-Golabi (2008) KF/Al2O3 as
a Highly Efficient, Green, Heterogeneous, and Reusable Catalytic System for the
Solvent-Free Synthesis of Carboacyclic Nucleosides via Michael Addition Reaction,

Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 39:1, 139-157, DOI: 10.1080/00397910802369711
To link to this article: http://dx.doi.org/10.1080/00397910802369711
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Synthetic Communications1, 39: 139–157, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802369711
KF/Al2O3 as a Highly Efficient, Green,
Heterogeneous, and Reusable Catalytic System
for the Solvent-Free Synthesis of Carboacyclic
Nucleosides via Michael Addition Reaction
Abdolkarim Zare,1 Alireza Hasaninejad,2 Mohammad Hassan
Beyzavi,3 Ahmad Reza Moosavi Zare,1 Ali Khalafi-Nezhad,3
Fatemeh Asadi,1 Leila Baramaki,1 Sedigheh Jomhori-Angali,1 and
Rokhsareh Ghaleh-Golabi1
1Department of Chemistry, College of Sciences, Payame Noor University
(PNU), Bushehr, Iran
2Department of Chemistry, Faculty of Sciences, Persian Gulf University,
Bushehr, Iran
3Department of Chemistry, College of Sciences,
Shiraz University, Shiraz, Iran
Abstract: KF=Al2O3 acts as an efficient catalytic system for the synthesis of
carboacyclic nucleosides via Michael addition of pyrimidine and purine
nucleobases to a,b-unsaturated esters under solvent-free and microwave condi-
tions. Using this method, the title compounds are produced in good to excellent
yields and short reaction times.
Keywords: Carboacyclic nucleoside, KF=Al2O3, Michael addition, microwave,
nucleobase, solvent-free
Received June 15, 2008.
Address correspondence to Abdolkarim Zare, Department of Chemistry,
College of Sciences, Payame Noor University (PNU), Bushehr 1698, Iran. E-mail:
abdolkarimzare@yahoo.com or Alireza Hasaninejad, Department of Chemistry,
Faculty of Sciences, Persian Gulf University, Bushehr 75169, Iran. ahassaninejad@
yahoo.com
139

140
A. Zare et al.
In recent years, the use of solid-supported catalysts has become popular
because of their unique properties such as enhanced reactivity as well as
selectivity, straightforward workup, recyclability of the catalyst, and eco-
friendly reaction conditions.[1,2] Alumina-supported potassium fluoride
(KF) is one of the most interesting of these green catalysts because it
has surface properties that suggest that very rich organic reactions may
occur there.[2] KF=Al2O3 is an inexpensive, commercially available, reu-
sable, and environmentally benign catalyst that has been used in various
organic transformations, such as acetylation of amines, alcohols, and
phenols,[2a] preparation of amides from nitriles,[2b] cycloaddition of azo-
methine ylides,[2c] hydrothilation of alkynes,[2d] alkylation and arylation
reactions,[2e–g] conversion of aldehydes to nitriles,[2h] deformylation of
N-arylformamides,[2i] desilylation reactions,[2j] synthesis of pyrano[3,2-
c]pyran derivatives,[2k] and synthesis of oxazolidinones,[2l] among
others.[2m] Nevertheless, most of the existing processes in organic synth-
esis involve toxic and volatile organic solvents as reaction media, and
these are environmentally unacceptable from a green chemistry view-
point. One of the most useful techniques to solve this problem is the
use of solvent-free conditions that make synthesis simpler, save energy,
and prevent solvent waste, hazards, and toxicity.[3] Together with the
removal of solvent, unconventional activation methods, mainly micro-
wave irradiation, have been applied as powerful techniques to reduce
reaction times and to increase yields.[3] Consequently, the combination
of safe catalysis with the use of solvent-free technique under microwave
irradiation represents a suitable way toward the so-called ideal synthesis.
Carboacyclic nucleosides have attracted much interest because of
their potential use as anticancer,[4a] antibiotic,[4b] antiviral,[4c] and anti-
psychotic agents[4d] and receptors.[4e] The Michael addition of nucleo-
bases to electrophilic multiple bonds has been used as a useful route
toward carboacyclic nucleosides synthesis.[5] Several bases and catalysts
have been applied to achieve this transformation, such as ZnO=tetra-
butylammonium bromide,[5a] 1,4-diazabicyclo[2,2,2]octane,[5b] PBu3,[5c]
[bmim]OH,[5d] K2CO3,[5e] t-BuOK,[5f] NaOEt,[5g] and enzyme.[5h] It is
worth noting that the methods that have been established for Michael
reaction of nucleobases suffer one or more of the following drawbacks:
long reaction times, low yields, low selectivity, the use of expensive
catalysts, the use of stoichiometric amounts of catalyst, application of
only unhindered electrophilic alkenes, and no agreement with the green
chemistry protocols. Moreover, some methods can be used for Michael
reaction of only pyrimidines or only purines. Also, in some reports,
Michael reaction of nucleobases has not been studied systematically.
With these facts in mind and also in extension of our previous studies
on nucleoside chemistry,[1e,5a,5b,6] we report here a simple method for the

Synthesis of Carboacyclic Nucleosides
141
Scheme 1. Michael addition of uracil as a pyrimidine nucleobase to ethyl acrylate.
synthesis of carboacyclic nucleosides via Michael addition of pyrimidine
and purine nucleobases to a,b-unsaturated esters in the presence of
KF=Al2O3 and tetrabutylammonium bromide (TBAB) under solvent-free
and microwave conditions ( Schemes 1 and 2). It is important to note that
this method has none of the mentioned disadvantages at all.
As previously mentioned, KF=Al2O3 has been applied as a highly
efficient catalytic system for different organic transformations.[2] This
subject encouraged us to use it for the synthesis of N-alkyl derivatives
of nucleobases (carboacyclic nucleosides) via Michael addition of nucleo-
bases to a,b-unsaturated esters. Therefore, first we studied Michael addi-
tion of uracil (2 mmol) to ethyl acrylate (2.2 mmol) in the presence of
different molar ratios of KF=Al2O3 to substrate and TBAB (1 mmol)
under microwave irradiation (200 W, max. 100 ꢀC) (Scheme 1, Table 1).
In this reaction, two products were produced: N1-alkylted and N1,N3-
dialkylated uracil. The aim of this work has synthesis of the N1-alkylated
products. As can be seen from Table 1, higher yield of the N1-alkyl uracil
was obtained when 12.5 mol% of KF=Al2O3 was applied. Incrementing
the proportion of the catalyst increased the yield of N1,N3-dialkylated
uracil (Table 1). We also examined the Michael reaction of 6-chloropurine
as a purine nucleobase and n-butyl acrylate in the presence of 12.5 mol%
KF=Al2O3 and TBAB, in which N9- and N7-alkylated 6-chloropurine
were obtained in 71 and 25%, respectively (Scheme 2). Changing the
molar ratio of the catalyst did not improve the selectivity. Thus, the best
Scheme 2. Michael addition of 6-chloropurine as a purine nucleobase to n-butyl
acrylate.

142
A. Zare et al.
Table 1. Effect of different molar ratios of KF=Al2O3 on the reaction of uracil
with ethyl acrylate in the presence of TBAB under microwave irradiation (200
W, max. 100 ꢀC)
Yielda (%)
Mol% of
KF=Al2O3
Time
(min)
N1-Alkylated product
(1a)
N1,N3-Dialkylated pruduct
(2a)
12.5
25
40
60
23
18
15
10
87
43
34
21
5
28
32
39
aIsolated yield.
proportion of KF=Al2O3 for Michael reaction of both pyrimidine and
purine nucleobases was 12.5 mol%. To recognize the efficiency of
KF=Al2O3 catalytic system, we tested the model reaction in the presence
of KF as well as Al2O3 separately. The results are summarized in Table 2.
As Table 2 indicates, in both conditions the reaction yields considerably
decreased. In another study, we investigated the effect of TBAB on
the Michael reaction between uracil and ethyl acrylate. The yield of the
target product decreased when TBAB was removed from the reaction
media (Table 2). Thus, TBAB has an essential effect on the progress of
the reaction. In general, TBAB melts at 100 ꢀC and creates
a
homogeneous reaction media.[5a,5b] Moreover, this quaternary
Table 2. Michael addition of uracil to ethyl acrylate using KF=TBAB,
Al2O3=TBAB, KF=Al2O3, and TBAB separately under microwave irradiation
(200 W, max. 100 ꢀC)
Yielda (%)
Catalytic
system
Time
(min)
N1-Alkylated product
(1a)
N1,N3-Dialkylated
pruduct (2a)
KF=TBAB
Al2O3=TBAB
KF=Al2O3
TBABc
30
25
30
25
32
57
41
64
Trace
Trace
Trace
10
b
aIsolated yield.
bThis reaction was carried out in the absence of TBAB.
cThis reaction was performed in the presence of TBAB without KF=Al2O3.

Synthesis of Carboacyclic Nucleosides
143
ammonium salt absorbs the microwave irradiation as well as generates in
situ heat and increases the temperature higher than its melting point.[5a,5b]
TBAB maybe also acts as a phase-transfer catalyst in our reaction.[3b]
Moreover, we examined the Michael addition of uracil to ethyl acrylate
in the presence of TBAB without KF=Al2O3 in which N1-alkylated
and N1,N3-dialkylated Michael adducts were obtained in 64 and 10%,
respectively (Table 2).
To compare the efficiency of the solvent-free procedure versus solu-
tion conditions, we studied the model reaction in some solvents. Thus, a
mixture of uracil (2 mmol), ethyl acrylate (2.2 mmol), KF=Al2O3
(0.25 mmol), and TBAB (1 mmol) was irradiated in a microwave oven
(200 W, max. 100 ꢀC) in different solvents (5 mL) (Table 3). As is shown
in Table 3, the yields of N1-alkylated uracil as well as selectivities
decreased in solution conditions.
We also studied the capability and efficiency of microwave heating in
comparison with conventional heating on the Michael reaction. For this
purpose, compounds 1a as well as 2a were also prepared via Michael
addition of uracil to ethyl acrylate in the presence of KF=Al2O3 and
TBAB in an oil bath (100 ꢀC). This reaction afforded compounds 1a
and 2a in 48 and 22% respectively within 240 min. Thus, microwave
irradiation has an essential influence on the progress and selectivity of
the Michael reaction.
To realize the generality and scope of our method, different pyrimi-
dine and purine nucleobases were introduced to structurally diverse a,b-
unsaturated esters. The results are displayed in Table 4. As Table 4
shows, all reactions proceeded efficiently, and the desired carboacyclic
nucleosides were obtained in good to excellent yields and short reaction
times. It has been observed that the bulkiness of alkoxy group (-OR)
Table 3. Comparative Michael addition of uracil to ethyl acrylate using
KF=Al2O3 and TBAB in different solvents versus the solvent-free conditions
promoted by microwave irradiation (200 W, max. 100 ꢀC)
Yielda (%)
Time
(min)
N1-Alkylated product
(1a)
N1,N3-Dialkylated
pruduct (2a)
Solvent
DMSO
DMF
o-Xylene
None
20
20
30
23
48
73
16
87
25
11
Trace
5
aIsolated yield.

144
A. Zare et al.
Table 4. Synthesis of carboacyclic nucleosides via Michael addition of pyrimidine
and purine nucleobases to a,b-unsaturated esters in the presence of KF=Al2O3
and TBAB under solvent-free and microwave conditions
MW Power
(W)
T
Time Yielda
Entry
1
Product
(ꢀC) (min)
(%)
200
200
200
100
100
100
23
23
25
87
2
3
89
85
4
200
200
200
100
100
100
26
32
26
84
80
85
5
6b
(Continued )

Synthesis of Carboacyclic Nucleosides
145
Table 4. Continued
MW Power
(W)
T
Time Yielda
Entry
7b
Product
(ꢀC) (min)
(%)
200
200
300
100
100
130
21
25
14
90
8b
84
70
9b
10b
400
300
130
130
12
17
59
64
11b
12b
200
100
25
81
(Continued )

146
A. Zare et al.
Table 4. Continued
MW Power
(W)
T
Time Yielda
Entry
13
Product
(ꢀC) (min)
(%)
300
120 18
71
25
73
14
300
120
25
21
90
15b
300
300
100
130
38
21
16
94
(Continued )

Synthesis of Carboacyclic Nucleosides
147
Table 4. Continued
MW Power
(W)
T
Time Yielda
Entry
17
Product
(ꢀC) (min)
(%)
300
130
26
85
18b
400
140
17
75
19b
400
140
22
66
aIsolated yield.
bIn this reaction, the a,b-unsaturated ester=nucleobase ratio (mol=mol) was
1.1=1.
of a,b-unsaturated esters had little effect on the Michael reaction (Table 4,
entries 1–5 and 17). The yields slightly decreased, and the reaction times
enhanced when nucleobases were reacted with esters possessing bulky
alkoxy group. The presence of substituents (Me and F, Br) on 5-position
of pyrimidine nucleobases did not affect considerably on the reaction
times and the yields (Table 4, entries 6–8). Furthermore, lower yield of
the products were obtained when nucleobases were added to the sterically
hindered a,b-unsaturated esters, ethyl methacrylate, and ethyl crotonate
(Table 4, entries 9–11, 18, and 19). Among the purine nucleobases,
adenine afforded dominantly N9 isomer (Table 4, entries 15–19); how-
ever, 6-chloropurine and hypoxanthine gave a mixture of N7 and N9 iso-
mers (Table 4, entries 13 and 14).
The efficiency and capacity of our method was compared with the
reported methods for the Michael reaction of nucleobases (Table 5).
For this purpose, we have tabulated the results of the reported methods

148
A. Zare et al.
Table 5. Comparative synthesis of compounds 1b, 1i, 1j, 3d, 3f, and 3g using the
reported methods versus our method
Khalafi-
Nezhad
et al.[5b]
Present
method
Cai et al.[5h]
Zare et al.[5a]
Time
Compound (min) (min)
Time Yield Yield Time Yield Time Yield
(min)
(%)
(%)
(min)
(%)
(%)
1b
1i
720
—
—
—
—
—
44
—
—
—
—
—
6
10
9
8
12
10
85
40
27
73
38
24
25
20
15
20
15
20
93
48
41
74
37
29
23
14
12
21
17
22
89
70
59
94
75
66
1j
3d
3f
3g
for the preparation of compounds 1b, 1i, 1j, 3d, 3f, and 3g. As Table 5
demonstrates, our method significantly improved Michael addition of
pyrimidine nucleobases to substituted a,b-unsaturated esters as well
as Michael addition of purines to substituted and unsubstituted a,b-
unsaturated esters.
One of the most interesting properties of KF=Al2O3 is its ease of
recycling. The yields of compounds 1a and 2a (model compounds) in
the second, third, and fourth uses of the catalyst were almost as high
as in the first use.
In conclusion, we have introduced a highly efficient catalyst for
Michael addition of nucleobases to a,b-unsaturated esters in the absence
of solvent under microwave irradiation. The promising points for the pre-
sented methodology are efficiency, generality, high yield, high selectivity,
short reaction time, ease of handling and low cost of the catalyst, cleaner
reaction profile, ease of product isolation, simplicity, potential for recy-
cling the catalyst, and finally agreement with the green chemistry proto-
cols, which makes it a useful and attractive process for the synthesis of
carboacyclic nucleosides.
EXPERIMENTAL
All chemicals were purchased from Merck or Fluka Chemical Compa-
nies. All reactions were carried out using laboratory microwave oven
(MW3000, Landgraf Company, Germany). IR spectra were run on a
Shimadzu FTIR-8300 spectrophotometer. The 1H NMR (250 MHz)
and 13C NMR (62.5 mhz) were run on a Bruker Avance DPX-250,

Synthesis of Carboacyclic Nucleosides
149
FT-NMR spectrometer (d in ppm). Mass spectra were recorded on a
Shimadzu GC MS-QP 1000 EX apparatus. Microanalyses were
performed on a Perkin-Elmer 240-B microanalyzer. Melting points were
recorded on a Buchi B-545 apparatus in open capillary tubes.
¨
General Procedure for the Preparation of the KF/Al2O3 Catalytic System
A mixture of KF (0.291 g, 5 mmol) and Al2O3 (0.510, 5 mmol) was
ground vigorously to give the KF=Al2O3 catalytic system as a white
powder (0.801 g).
General Procedure for Michael Addition of Nucleobases to
a,b-Unsaturated Esters
To a well-ground mixture of nucleobase (2 mmol), KF=Al2O3 (0.04 g,
0.25 mmol, 12.5 mol%), and TBAB (1 mmol, 0.322 g) in a microwave ves-
sel, a,b-unsaturated ester (2.1 mmol) was added and mixed carefully with
a small rod. The resulting mixture was irradiated in a microwave oven for
the powers, the temperatures, and the times reported in Table 4. Then,
the reaction mixture was cooled to room temperature and suspended in
EtOAc (50 mL) and filtered, and the filtrate was washed with water
(2 ꢁ 50 mL) and dried with MgSO4. The solvent was evaporated, and
the crude product was purified by column chromatography on silica
gel eluted with EtOAc-n-hexane. After isolation of the product, the
remaining KF=Al2O3 was reused.
Data
Ethyl 3-(2,4-Dioxo-3,4-dihydropyrimidin-1(2H)-yl)propanoate (1a)
Column chromatography on silica gel eluted with EtOAc=n-hexane
(2:1) gave a colorless solid; mp 77–79 ꢀC (lit.[5a] mp 77–79 ꢀC);1H NMR
(CDCl3): d ¼ 1.25 (t, 3H, J ¼ 7.0 Hz, CH3), 2.74 (t, 2H, J ¼
6.0 Hz, O¼CCH2), 3.85 (t, 2H, J ¼ 6.0 Hz, NCH2), 4.11 (q, 2H,
J ¼ 7.0 Hz, OCH2), 5.64 (d, 1H, J ¼ 7.9 Hz, H-5 of uracil), 7.26 (d, 1H,
J ¼ 7.9 Hz, H-6 of uracil), 10.19 (s, 1H, NH).
Ethyl 3-[3-(2-Ethoxycarbonyl-ethyl)-2,4-dioxo-3,4-dihydro-2H-pyrimidine-
1-yl]propanoate (2a)
Column chromatography on silica gel eluted with EtOAc=n-hexane (2:1)
1
gave a pale yellow oil (lit.[6b] oil); H NMR (CDCl3): d ¼ 1.13 (t, 6H,

150
A. Zare et al.
J ¼ 7.1 Hz, 2CH2CH3), 2.49 (t, 2H, J ¼ 7.5 Hz), 2.65 (t, 2H, J ¼ 6.0 Hz),
3.89 (t, 2H, J ¼ 6.0 Hz,), 3.95–4.08 (complex, 6H), 5.57 (d, 1H, J ¼ 7.9 Hz,
Hz, H-5 of uracil), 7.28 (d, 1H, J ¼ 7.9 Hz, H-6 of uracil).
Butyl 3-(2,4-Dioxo-3,4-dihydropyrimidin-1(2H)-yl)propanoate (1b)
Column chromatography on silica gel eluted with EtOAc=n-hexane (2:1)
gave a colorless solid; mp 62–64ꢀC (lit.[5a] mp 61–63 ꢀC);1H NMR (CDCl3):
d ¼ 0.92 (t, 3H, J ¼ 6.8 Hz, CH3), 1.35 (m, 2H, CH3CH2), 1.56 (m, 2H,
CH3CH2CH2), 2.72 (t, 2H, J¼ 5.9 Hz, O¼CCH2), 3.80 (t, 2H, J ¼ 5.9 Hz,
NCH2), 4.09 (t, 2H, J ¼ 6.9 Hz, OCH2), 5.66 (d, 1H, J ¼ 7.9 Hz, H-5 of
uracil), 7.25 (d, 1H, J ¼ 7.9 Hz, H-6 of uracil), 10.22 (s, 1H, NH).
Benzyl 3-(2,4-Dioxo-3,4-dihydropyrimidin-1(2H)-yl)propanoate (1c)
Column chromatography on silica gel and eluting with EtOAc-n-hexane
(2:1) gave a pale yellow buff (lit.[5a] buff); 1H NMR (CDCl3): d ¼ 2.73 (t,
2H, J ¼ 5.9 Hz, O¼CCH2), 3.77 (t, 2H, J ¼ 5.9 Hz, NCH2), 4.89 (s, 2H,
OCH2), 5.56 (d, 1H, J ¼ 7.9 Hz, H-5 of uracil), 7.09–7.23 (complex, 6H,
H-1 to H-5 of phenyl group and H-6 of uracil), 10.32 (br, 1H, NH).
Phenethyl 3-(2,4-Dioxo-3,4-dihydropyrimidin-1(2H)-yl)propanoate (1d)
Column chromatography on silica gel eluted with EtOAc=n-hexane (2:1)
1
gave a pale yellow buff (lit.[5a] buff); H NMR (CDCl3): d ¼ 2.71 (t, 2H,
J ¼ 5.8 Hz, O¼CCH2), 2.86 (t, 2H, J ¼ 7.0 Hz, PhCH2), 3.81 (t, 2H,
J ¼ 5.8 Hz, NCH2), 4.32 (t, 2H, J ¼ 7.0 Hz, OCH2), 5.60 (d, 1H,
J ¼ 7.9 Hz, H-5 of uracil), 7.11–7.25 (complex, 6H, H-1 to H-5 of phenyl
group and H-6 of uracil), 10.26 (s, 1H, NH).
2-Hydroxy-3-(2-Methoxyphenoxy)propyl 3-(2,4-Dioxo-3,4-
dihydropyrimidin-1(2H)-yl)propanoate (1e)
Column chromatography on silica gel eluted with EtOAc=n-hexane (2:1)
gave a pale yellow oil; IR (neat): 3468, 3170, 3063, 2972, 1732, 1684,
1647 cmꢂ1
;
1H NMR (CDCl3): d 2.75 (t, 2H, J ¼ 5.9 Hz, O¼CCH2),
3.66 (s, 3H, CH3), 3.81–3.92 (m, 5H), 4.15–4.26 (m, 3H), 5.63 (d, 1H,
J ¼ 8.0 Hz, H-5 of uracil), 6.71–6.79 (m, 4H, H-2 to H-4 of phenyl aryl
group), 7.20 (d, 1H, J ¼ 8.0 Hz, H-6 of uracil), 10.25 (s, 1H, NH); 13C
NMR (CDCl3): d ¼ 55.9, 65.4, 68.3, 70.8, 36.6, 45.9, 102.3, 112.3,

Synthesis of Carboacyclic Nucleosides
151
114.6, 121.2, 122.0, 145.0, 147.5, 149.7, 151.6, 164.0, 170.6; MS:
m=z ¼ 364 (Mþ), Anal. calcd. for C17H20N2O7: C, 56.04; H, 5.53; N,
7.69. Found: C, 56.22; H, 5.29; N, 7.52.
Ethyl 3-(5-Methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)propanoate
(1f)
Column chromatography on silica gel eluted with EtOAc=n-hexane (2:1)
1
gave a colorless solid; mp 146–148 ꢀC (lit.[5h] mp 149–150 ꢀC); H NMR
(CDCl3): d ¼ 1.24 (t, 3H, J ¼ 7.1 Hz, CH2CH3), 1.88 (s, 3H, CH3), 2.75
(t, 2H, J ¼ 6.0 Hz, O¼CCH2), 3.83 (t, 2H, J ¼ 6.0 Hz, NCH2), 4.12 (q,
2H, J ¼ 7.1 Hz, OCH2), 7.25 (s, 1H, H-6 of thymine), 10.19 (s, 1H, NH).
Ethyl 3-(5-Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)propanoate
(1g)
Column chromatography on silica gel eluted with EtOAc=n-hexane
(2:1) gave
a
colorless solid; mp 122–124 ꢀC (lit.[5h] mp 124–
126 ꢀC);1H NMR (CDCl3): d ¼ 1.22 (t, 3H, J ¼ 7.1 Hz, CH3), 2.79 (t,
2H, J ¼ 5.7 Hz, O¼CCH2), 3.80 (t, 2H, J ¼ 5.7 Hz, NCH2), 4.10 (q,
2H, J ¼ 7.1 Hz, OCH2), 7.28 (d, 1H, J ¼ 6.7 Hz, H-6 of 5-fluorouracil),
10.25 (s, 1H, NH).
Ethyl 3-(5-Bromo-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)propanoate
(1h)
Column chromatography on silica gel and eluting with EtOAc=n-hexane
(2:1) gave a pale yellow solid; mp 140–145 ꢀC (dec.) [(lit.[5h] mp 143–
150 ꢀC (dec.)];1H NMR (CDCl3): d ¼ 1.25 (t, 3H, J ¼ 7.0 Hz, CH3), 2.79
(t, 2H, J ¼ 5.8 Hz, O¼CCH2), 3.82 (t, 2H, J¼ 5.8 Hz, NCH2), 4.12 (q, 2H,
J¼ 7.0 Hz, OCH2), 7.61 (s, 1H, H6 of 5-bromouracil), 10.27 (s, 1H, NH).
Ethyl 3-(2,4-Dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methylpropanoate
(1i)
Column chromatography on silica gel eluted with EtOAc=n-hexane (2:1)
1
gave a pale yellow oil (lit.[5b] oil); H NMR (CDCl3): d ¼ 1.16–1.21 (m,
6H, CH2CH3 and CHCH3), 2.95 (m, 1H, O¼CCH), 3.64 (m, 1H, one
H of NCH2), 3.82 (m, 1H, one H of NCH2), 4.12 (q, 2H, J ¼ 7.0 Hz,
OCH2), 5.63 (d, 1H, J ¼ 7.9 Hz, H-5 of uracil), 7.22 (d, 1H, J ¼ 7.9 Hz,
H-6 of uracil), 10.22 (s, 1H, NH).

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A. Zare et al.
Ethyl 3-(2,4-Dioxo-3,4-dihydropyrimidin-1(2H)-yl)butanoate (1j)
Column chromatography on silica gel eluted with EtOAc=n-hexane (2=1)
gave a pale yellow solid; mp 116–118 ꢀC (lit.[5b] mp 116–118 ꢀC);1H NMR
(CDCl3): d ¼ 1.22 (t, 3H, J ¼ 7.0 Hz, CH2CH3), 1.39 (d, 3H, J ¼ 6.9 Hz,
CHCH3), 2.65 (m, 1H, one H of O¼CCH2), 2.86 (m, 1H, one H of
O¼CCH2), 4.11 (q, 2H, J ¼ 7.0 Hz, OCH2), 4.65 (m, 1H, CH3CH), 5.65
(d, 1H, J ¼ 7.9 Hz, H-5 of uracil), 7.25 (d, 1H, J ¼ 7.9 Hz, H-6 of uracil),
10.24 (s, 1H, NH).
Ethyl 2-Methyl-3-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)
propanoate (1k)
Column chromatography on silica gel and eluting with EtOAc=n-hexane
1
(2:1) gave a pale yellow solid; mp 41–43 ꢀC (lit.[5a] 40–42 ꢀC); H NMR
(CDCl3): d ¼ 1.10–1.17 (complex, 6H, CHCH3 and CH2CH3), 1.95 (s,
3H, CH3 of thymine), 2.94 (m, 1H, O¼CCH), 3.61 (m, 1H, one H of
NCH2), 3.82 (m, 1H, one H of NCH2), 4.08 (q, 2H, J ¼ 7.0 Hz, OCH2),
7.16 (s, 1H, H-6 of thymine), 10.21 (1H, br, NH).
Ethyl 3-(4-Acetamido-2-oxopyrimidin-1(2H)-yl)propanoate (1l)
Column chromatography on silica gel and eluting with EtOAc=n-hexane
1
(2:1) gave a colorless solid; mp 127–129 ꢀC (lit.[5h] mp 130–131 ꢀC). H
NMR (CDCl3): d ¼ 1.21 (t, 3H, J ¼ 7.0 Hz, CH2CH3), 2.19 (s, 3H,
O¼CCH3), 2.82 (t, 2H, J ¼ 5.8 Hz, O¼CCH2), 3.97 (t, 2H, J ¼ 5.8 Hz,
NCH2), 4.09 (t, 2H, J ¼ 7.0 Hz, OCH2), 7.25 (d, 1H, J ¼ 7.3 Hz), 7.73
(d, 1H, J ¼ 7.3 Hz), 9.25 (s, 1H, NH).
Butyl 3-(6-Chloro-9H-purin-9-yl)propanoate (3a)
Column chromatography on silica gel eluted with EtOAc=n-hexane (1:1)
gave a colorless oil (lit.[5a] oil); 1H NMR (CDCl3): d ¼ 0.90 (t, 3H,
J ¼ 6.7 Hz, CH3), 1.33 (m, 2H, CH3CH2), 1.56 (m, 2H, CH3CH2CH2),
2.95 (t, 2H, J ¼ 5.8 Hz, O¼CCH2), 4.09 (t, 2H, J ¼ 6.9 Hz, OCH2), 4.61
(t, 2H, J ¼ 5.8 Hz, NCH2), 8.52 (1H, s, H-8 of 6-chloropurine), 8.99
(s, 1H, H-2 of 6-chloropurine).
Butyl 3-(6-Chloro-9H-purin-7-yl)propanoate (4a)
Column chromatography on silica gel eluted with EtOAc=n-hexane (1:1)
1
gave a pale yellow solid; mp 59–61 ꢀC (lit.[5a] mp 60–62 ꢀC); H NMR

Synthesis of Carboacyclic Nucleosides
153
(CDCl3): d ¼ 0.93 (t, 3H, J ¼ 6.8 Hz, CH3), 1.35 (m, 2H, CH3CH2), 1.60
(m, 2H, CH3CH2CH2), 2.99 (t, 2H, J ¼ 5.8 Hz, O¼CCH2), 4.11 (t, 2H,
J ¼ 6.7 Hz, OCH2), 4.87 (t, 2H, J ¼ 5.8 Hz, NCH2), 8.61 (s, 1H,
H-8 of 6-chloropurine), 9.09 (s, 1H, H-2 of 6-chloropurine).
Butyl 3-(6-Oxo-1,6-dihydropurin-9-yl)propanoate (3b)
Column chromatography on silica gel eluted with EtOAc=n-hexane (3:1)
gave a colorless solid; mp 84–86 ꢀC (lit.[5a] mp 83–85 ꢀC); 1H NMR
(CDCl3): d ¼ 0.92 (t, 3H, J ¼ 6.8 Hz, CH3), 1.35 (m, 2H, CH3CH2),
1.58 (m, 2H, CH3CH2CH2), 2.87 (t, 2H, J ¼ 5.8 Hz, O¼CCH2), 4.12
(t, 2H, J ¼ 6.9 Hz, OCH2), 4.52 (t, 2H, J ¼ 5.8 Hz, NCH2), 7.99 (s, 1H,
H-8 of hypoxanthine), 8.56 (s, 1H, H-2 of hypoxanthine), 10.43 (s, 1H,
NH).
Butyl 3-(6-Oxo-1,6-dihydropurin-7-yl)propanoate (4b)
Column chromatography on silica gel eluted with EtOAc=n -hexane (3:1)
1
gave a colorless solid; mp 99–102 ꢀC (lit.[5a] mp 99–102 ꢀC); H NMR
(CDCl3): d ¼ 0.90 (t, 3H, J ¼ 6.8 Hz, CH3), 1.38 (m, 2H, CH3CH2),
1.59 (m, 2H, CH3CH2CH2), 2.90 (t, 2H, J ¼ 5.9 Hz, O¼CCH2), 4.08
(t, 2H, J ¼ 6.8 Hz, OCH2), 4.74 (t, 2H, J ¼ 5.9 Hz, NCH2), 8.10 (s, 1H,
H-8 of hypoxanthine), 8.64 (s, 1H, H-2 of hypoxanthine), 10.48 (s, 1H,
NH).
Ethyl 3-(6-Amino-9H-purin-9-yl)propanoate (3c)
Column chromatography on silica gel eluted with EtOAc=n-hexane (3:1)
1
gave a colorless solid; mp 164–166 ꢀC (lit.[5g] mp 167–168 ꢀC); H NMR
(CDCl3): d ¼ 1.19 (t, 3H, J ¼ 6.9 Hz, CH3), 2.95 (t, 2H, J ¼ 5.9 Hz,
O¼CCH2), 4.12 (t, 2H, J ¼ 6.9 Hz, OCH2), 4.49 (t, 2H, J ¼ 5.9 Hz,
NCH2), 6.41 (s, 2H, NH2), 7.96 (s, 1H, H-2 of adenine), 8.45 (s, 1H,
H-8 of adenine).
Butyl 3-(6-Amino-9H-purin-9-yl)propanoate (3d)
Column chromatography on silica gel eluted with EtOAc=n-hexane (3:1)
gave a colorless solid; mp 135–137 ꢀC (lit.[5b] 134–136 ꢀC); 1H NMR
(CDCl3): d ¼ 0.93 (t, 3H, J ¼ 6.7 Hz, CH3), 1.36 (m, 2H, CH3CH2),
1.58 (m, 2H, CH3CH2CH2), 2.93 (t, 2H, J ¼ 5.8 Hz, O¼CCH2), 4.11 (t,

154
A. Zare et al.
2H, J ¼ 6.8 Hz, OCH2), 4.53 (t, 2H, J ¼ 5.8 Hz, NCH2), 6.38 (s, 2H,
NH2), 7.99 (s, 1H, H-2 of adenine), 8.40 (s, 1H, H-8 of adenine).
2-Hydroxy-3-(2-methoxyphenoxy)propyl
propanoate (3e)
3-(6-Amino-9H-purin-9-yl)
Column chromatography on silica gel eluted with EtOAc=n-hexane (3:1)
gave pale yellow oil; IR (neat): 3452, 3291, 3115, 3069, 2941, 1728 cmꢂ1
;
1H NMR (CDCl3): d ¼ 2.96 (t, J ¼ 5.8 Hz, 2H, O¼CCH2), 3.72 (s, 3H,
CH3), 3.92–4.03 (m, 3H), 4.19–4.29 (m, 3H), 4.46 (t, 2H, J ¼ 5.8 Hz,
NCH2), 6.47 (s, 2H, NH2), 6.68–6.77 (m, 4H), 7.94 (s, 1H, H-2 of ade-
nine), 8.46 (s, 1H, H-8 of adenine);13C NMR (CDCl3): d ¼ 39.4, 46.9,
56.3, 64.9, 68.6, 71.0, 113.1, 114.8, 120.2, 121.9, 122.7, 140.6, 146.3,
149.4, 150.3, 153.0, 155.8, 171.4; MS: m=z ¼ 387 (Mþ), Anal. calcd. for
C18H21N5O5: C, 55.81; H, 5.46; N, 18.08. Found: C, 56.04; H, 5.31; N,
18.26.
Ethyl 3-(6-Amino-9H-purin-9-yl)-2-methylpropanoate (3f)
Column chromatography on silica gel eluted with EtOAc=n-hexane (3:1)
1
gave a colorless solid; mp 133–135 ꢀC (lit.[5b] mp 134–137 ꢀC); H NMR
(CDCl3): d ¼ 1.12–1.21 (m, 6H, CH2CH3 and CHCH3), 3.13 (m, 1H,
O¼CCH), 4.09 (q, 2H, J ¼ 6.9 Hz, OCH2), 4.22 (m, 1H, one H of
NCH2), 4.43 (m, 1H, one H of NCH2), 6.24 (s, 2H, NH2), 7.83 (s, 1H,
H-2 of adenine), 8.35 (s, 1H, H-8 of adenine).
Ethyl 3-(6-Amino-9H-purin-9-yl)butanoate (3g)
Column chromatography on silica gel eluted with EtOAc=n-hexane (3:1)
gave a colorless solid; mp 101–103 ꢀC (lit.[5b] mp 100–101 ꢀC);1H NMR
(CDCl3): d ¼ 1.14 (t, 3H, J ¼ 6.8 Hz, CH2CH3), 1.66 (d, 3H, J ¼ 4.7 Hz,
CHCH3), 2.89 (m, 1H, one H of O¼CCH2), 3.15 (m, 1H, one H of
O¼CCH2), 4.06 (q, 2H, J ¼ 6.8 Hz, OCH2), 4.97 (m, 1H, NCH), 6.31
(s, 2H, NH2), 7.80 (s, 1H, H-2 of adenine), 8.27 (s, 1H, H-8 of adenine).
ACKNOWLEDGMENTS
We appreciate Payame Noor University (PNU) and Persian Gulf
University Research Councils for the financial support of this work.

Synthesis of Carboacyclic Nucleosides
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