Zinc oxide-tetrabutylammonium bromide tandem as a highly efficient, green, and reusable catalyst for the Michael addition of pyrimidine and purine nucleobases to α,β-unsaturated esters under solvent-free conditions

Article abstract of DOI:10.1139/V08-022

An efficient procedure for the synthesis of carboacyclic nucleosides via microwave-assisted Michael addition of pyrimidine and purine nucleobases to α,β-unsaturated esters in the presence of catalytic amounts of zinc oxide (ZnO) and tetrabutylammonium bro

Full text of DOI:10.1139/V08-022

317
Zinc oxide-tetrabutylammonium bromide tandem
as a highly efficient, green, and reusable catalyst
for the Michael addition of pyrimidine and purine
nucleobases to ␣,␤-unsaturated esters under
solvent-free conditions
Abdolkarim Zare, Alireza Hasaninejad, Mohammad Hassan Beyzavi,
Abolfath Parhami, Ahmad Reza Moosavi Zare, Ali Khalafi-Nezhad, and
Hashem Sharghi
Abstract: An efficient procedure for the synthesis of carboacyclic nucleosides via microwave-assisted Michael addition
of pyrimidine and purine nucleobases to α,β-unsaturated esters in the presence of catalytic amounts of zinc oxide (ZnO)
and tetrabutylammonium bromide (TBAB) is described. The reactions proceed rapidly in good to excellent yields.
Key words: ZnO–TBAB, green chemistry, Michael addition, nucleobase, solvent-free, microwave.
Résumé : On a mis au point ne méthode efficace de réaliser la synthèse de nucléosides carboacycliques en faisant
appel des additions de Michael assistées par les microondes de nucléobases purines et pyrimidines sur des esters α,β-
insaturés en présence d’une quantité catalytique d’oxyde de zinc (ZnO) et de bromure de tétrabutylammonium (BTBA).
Les réactions se produisent rapidement avec des rendements allant de bons à excellents.
Mots-clés : oxyde de zinc–bromure de tétrabutylammonium, chimie verte, addition de Michael, nucléobase, sans
solvant, microonde.
[Traduit par la Rédaction] Zare et al. 324
Introduction
strong base to activate nucleobases. For this purpose, bases
such as [bmim]OH (9a), 1,4-diazabicyclo[2,2,2]octane
(DABCO) (9b), NaOEt (9c), K2CO3 (9d, 9e), and t-BuOK
(9f ) have been used. Moreover, an enzyme can also facili-
tate this transformation (9g).
The methods established for Michael addition of nucleo-
bases to electrophilic alkenes are associated with one or
more of the following drawbacks: (i) the use of solvents
such as DMF or DMSO in which the workup of the reaction
is not only cumbersome but also the green aspect of the re-
action is annihilated by using DMF, (ii) long reaction times,
(iii) low reaction yields and selectivity, (iv) the use of only
unsubstituted electrophilic alkenes, and (v) the use of
stoichiometric amounts of base or reagent.
N-substituted pyrimidine and purine nucleobases have at-
tracted much interest because of their potential use as
antineoplastic (1), antiviral (1), and anticancer agents (2).
Over the years, extensive efforts have been directed toward
the synthesis of new classes of N-substituted nucleobases
that brought about nucleoside subgroups with potent biologi-
cal activities, including acyclic (3), carboacyclic (4),
carbocyclic (5), aza (6), and thionucleosides (7). These com-
pounds are usually prepared by N-alkylation of nucleobases
with alkylating agents (8). Carboacyclic nucleosides can also
be synthesized via Michael addition of nucleobases to
electrophilic alkenes (9). This reaction normally requires a
Recently, mineral oxides have proved to be useful to
chemists in the laboratory and industry because of the good
activation of adsorbed compounds and reaction rate en-
hancement, selectivity, easier workup, recyclability of the
supports, and the eco-friendly reaction conditions (10, 11).
Zinc oxide (ZnO) is certainly one of the most interesting of
these oxides that has been applied in different organic trans-
formations (11). The coupling of microwave irradiation with
the use of catalysts or mineral-supported reagents provides
chemical processes with special attributes, such as enhanced
reaction rates, higher yields, better selectivity, and improved
ease of manipulation (12).
Received 23 June 2007. Accepted 24 January 2008. Published
on the NRC Research Press Web site at canjchem.nrc.ca on
10 March 2008.
A. Zare.1 Department of Chemistry, Payame Nour University
of Bushehr, Bushehr 1698, Iran.
A. Hasaninejad.1 Department of Chemistry, Faculty of
Sciences, Persian Gulf University, Bushehr 75169, Iran.
M.H. Beyzavi, A. Parhami, A.R. Moosavi Zare,
A. Khalafi-Nezhad, and H. Sharghi. Department of
Chemistry, College of Sciences, Shiraz University, Shiraz
71454, Iran.
1Corresponding authors (e-mail: abdolkarimzare@yahoo.com;
ahassaninejad@yahoo.com).
Having the above facts in mind and also in extension of
our previous studies on aza-Michael reactions (9b, 10a, 11a,
Can. J. Chem. 86: 317–324 (2008)
doi:10.1139/V08-022
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Can. J. Chem. Vol. 86, 2008
Scheme 1. Michael addition of pyrimidine nucleobases to α,β-unsaturated esters.
Scheme 2. Michael addition of N-(2-oxo-1,2-dihydropyrimidin-4-yl)acetamide to ethyl acrylate.
Scheme 3. Michael addition of purine nucleobase adenine to α,β-unsaturated esters.
11b, 13), solvent-free organic synthesis (8a, 9b, 13, 14), and
nucleoside derivatives synthesis (8a, 8b, 9b, 14c, 14d, 14h,
15), we report herein a clean, facile, and rapid solventless
method for Michael addition of pyrimidine and purine
nucleobases to α,β-unsaturated esters in the presence of cat-
alytic amount of ZnO–TBAB under microwave conditions
(Schemes 1–3).
Table 1. The influence of different catalysts on Michael addition
of uracil to n-butyl acrylate promoted by microwave irradiation
(200 W, max. 100 °C) under solvent-free conditions.
Catalyst
(mol%)
Time
(min)
Yield
(%)a
Entry
1
2
3
4
5
6
7
8
9
ZnO (10)-TBAB (20)
ZnO (20)-TBAB (20)
ZnO (50)-TBAB (20)
ZnO (100)-TBAB (20)
CaO (20)-TBAB (20)
MgO (20)-TBAB (20)
Basic Al2O3 (20)-TBAB (20)
ZnO (20)
30
25
20
15
30
30
25
40
25
81
93
76
62
31
16
40
39
64
Results and discussion
To optimize reaction conditions, the reaction of uracil
with n-butyl acrylate was studied as a model reaction to pro-
vide compound 1b. At first, the catalytic effect of various
catalysts in the presence of TBAB was examined under mi-
crowave conditions. The results are summarized in Table 1.
As shown in Table 1, the best results were obtained when
zinc oxide (20 mol%) was used. To understand the role of
TBAB in the reaction, Michael addition of uracil to n-butyl
acrylate was examined in the absence of TBAB under 200
W of microwave power (max. 100 °C). These conditions af-
forded the product in 39% yield after 40 min (Table 1, entry
8). Increasing the reaction time, the temperature, and the mi-
crowave power did not improve the reaction yield. Thus, the
presence of TBAB in the reaction media is critically signifi-
cant. In general, TBAB melts at 100 °C and creates a homo-
geneous reaction media whose resemblance is not far from
that of ionic liquids (8a, 9b, 11a, 13). Moreover, this quater-
nary ammonium salt absorbs the microwave irradiation as
well as generates in situ heat and increases the temperature
TBAB (20)
aIsolated yield.
higher than its melting point (100–103 °C) (8a, 9b, 11a, 13).
TBAB may also act as a phase-transfer catalyst in our reac-
tion (12a, 16). The model reaction was also tested in the
presence of only TBAB. This reaction afforded the product
in 64% within 25 min (Table 1, entry 9). Thus, ZnO and
TBAB did not efficiently catalyze the Michael reaction sep-
arately; however, these catalysts together (ZnO–TBAB) act
as an efficient catalytic system.
In another study, the model reaction was tested in several
solvents to compare the efficiency and capacity of the
solvent-free conditions with respect to solution conditions.
© 2008 NRC Canada

Zare et al.
319
Table 2. Comparative synthesis of compound 1b using solution
versus the solvent-free conditions in microwave conditions (200 W,
max. 100 °C).
N9 products in low yields (Table 3, entries 15 and 16). The
sites of N-addition were indicated by 1H and 13C NMR spec-
tral analysis. Several reports from the literature also con-
firmed these sites of N-addition (8a, 9b, 17).
Entry
Solvent
Time (min)
Yield (%)a
Ease of recycling is a useful feature of zinc oxide; for the
reaction of uracil with n-butyl acrylate no significant loss of
product yields was observed when ZnO was used after recy-
cling five times.
In summary, we have introduced an efficient new method
for the preparation of carboacyclic nucleosides as biologi-
cally interesting compounds via microwave-assisted Michael
addition of nucleobases to α,β-unsaturated esters. The ad-
vantages of this method are generality, high yields, short re-
action times, simplicity, low cost, and matches with green
chemistry protocols.
1
2
3
4
5
DMSO
DMF
HMPTA
o-Xylene
Solvent-free
35
35
35
35
25
82
77
42
23
93
aIsolated yield.
Thus, a mixture of uracil (2 mmol), ZnO (0.4 mmol), TBAB
(0.4 mmol), and n-butyl acrylate (2.2 mmol) was irradiated
in a microwave oven (200 W, max. 100 °C) in different sol-
vents (10 mL) (Table 2). As is clear from Table 2, lower
yields and longer reaction times were obtained in solution
conditions. Therefore, the solvent-free method is more effi-
cient.
Experimental
The capability and efficiency of the microwave heating
compared to conventional heating on the Michael reaction
was also investigated. For this purpose, compound 1b was
prepared via Michael reaction between uracil and n-butyl
acrylate in the presence of ZnO (20 mol%) and TBAB (20
mol%) under thermal conditions (100 °C). Using these con-
ditions, the Michael adduct (1b) was isolated in 71% yield
after 150 min. The reaction yield did not improve by in-
creasing the reaction time and the temperature. Therefore,
microwave irradiation is an essential factor to promote this
reaction.
To establish the generality and applicability of this
method, some pyrimidine and purine nucleobases were re-
acted with structurally diverse α,β-unsaturated esters to fur-
nish the corresponding Michael adducts in good to high
yields and short reaction times. The results are displayed in
Table 3.
All chemicals were purchased from Merck or Fluka chem-
ical companies. ZnO powder (GR for analysis, 99%) from
Merck company was used as a catalyst for all reactions. All
known compounds were identified by comparison of their
melting points and 1H NMR data with the authentic samples.
All reactions were carried out using laboratory microwave
oven (MW 3000, Landgraf Company, Germany). IR spectra
were run on a Shimadzu FTIR-8300 spectrophotometer, νmax
in cm–1. The 1H NMR (250 MHz) and 13C NMR (62.5 MHz)
were run on a Bruker Avanced DPX-250, FT-NMR spec-
trometer. Mass spectra were recorded on a Shimadzu GC
MS-QP 1000 EX apparatus. Microanalyses were performed
on a PerkinElmer 240-B microanalyzer. Melting points were
recorded on a Büchi B-545 apparatus in open capillary
tubes.
General procedure for the synthesis of compound 1b
To a well ground mixture of uracil (0.224 g, 2 mmol),
ZnO (0.033 g, 0.4 mmol), and TBAB (0.129 g, 0.4 mmol) in
a microwave vessel was added n-butyl acrylate (0.282 g,
2.2 mmol) and mixed carefully with a small rod. The mix-
ture was irradiated in a microwave oven for the powers, the
temperatures, and the times reported in Table 3. Afterward,
the reaction mixture was cooled to room temperature and
suspended in EtOAc (50 mL), 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 (2:1). After isolation of the product, the remainder
ZnO was reused.
The presence of substituents (Me, F, and Br) on the 5-
position of pyrimidine nucleobases had no significant effect
on results of the reaction (Table 3, entries 3–5). The struc-
tural influence of α,β-unsaturated esters on the reaction was
also investigated. Lower yields of products were obtained
when both pyrimidine or purine nucleobases were intro-
duced to sterically hindered α,β-unsaturated esters (Table 3,
entries 8–10, 17, and 18). In these cases, prolonging the re-
action times or increasing the microwave power or the tem-
perature had no effect on the efficiency of the reaction. The
bulkiness of alkoxy group (OR) affected the results of the
Michael reaction. The yields decreased and the reaction
times increased when nucleobase was added to esters
possessing bulky alkoxy groups (Table 3, entries 6 and 7).
Michael reaction of N-(2-oxo-1,2-dihydropyrimidin-4-
yl)acetamide was also efficiently achieved (Scheme 2 and
Table 3, entry 11).
Ethyl 3-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-
yl)propanoate (1a)
Interestingly, in our method, pyrimidine nucleobases were
regioselectively alkylated at the N1 positions. In these cases,
N1,N3-dialkylated pyrimidines were obtained in trace yields.
Moreover, pyrimidine nucleobases were not alkylated at the
O-positions. Among the purine nucleobases, adenine and N-
benzyl-9H-purin-6-amine were alkylated exclusively at the
N9 positions; however, Michael reaction of hypoxanthine
and 6-chloropurine afforded N7-adducts together with the
Column chromathography on silica gel and eluting with
EtOAc–n-hexane (2:1) gave a colorless solid. Isolated yield:
0.388 g (91%); mp 77–79 °C (lit. (9b) value mp 78–80 °C).
1H NMR (CDCl3, ppm) δ: 1.25 (t, 3H, J = 7.0 Hz, CH3),
2.74 (t, 2H, J = 6.0 Hz, O = CCH2), 3.85 (t, 2H J = 6.0 Hz,
NCH2), 4.11 (q, 2H, J = 7.0 Hz, OCH2), 5.64 (d, 1H, J =
7.9 Hz, H5 of uracil), 7.26 (d, 1H, J = 7.9 Hz, H6 of uracil),
10.19 (s, 1H, NH).
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Can. J. Chem. Vol. 86, 2008
Table 3. Michael addition of pyrimidine and purine nucleobases to α,β-unsaturated esters in the presence of ZnO (20 mol%) and
TBAB (20 mol%) under microwave irradiation.
7.9 Hz, H5 of uracil), 7.25 (d, 1H, J = 7.9 Hz, H6 of uracil),
10.22 (s, 1H, NH).
Butyl 3-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-
yl)propanoate (1b)
Column chromathography on silica gel and eluting with
EtOAc–n-hexane (2:1) gave a colorless solid. Isolated yield:
0.447 g (93%); mp 61–63 °C (lit. (9b) value mp 63–
65 °C).1H NMR (CDCl3, ppm) δ: 0.92 (t, 3H, J = 6.8 Hz,
CH3), 1.35 (m, 2H, CH3CH2), 1.56 (m, 2H, CH3CH2CH2),
2.72 (t, 2H, J = 5.9 Hz, O=CCH2), 3.80 (t, 2H, J = 5.9 Hz,
NCH2), 4.09 (t, 2H, J = 6.9 Hz, OCH2), 5.66 (d, 1H, J =
Ethyl 3-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-
yl)propanoate (1c)
Column chromathography on silica gel and eluting with
EtOAc–n-hexane (2:1) gave a colorless solid. Isolated yield:
0.403 g (89%); mp 146–148 °C (lit. (9g) value mp 149–
1
150 °C). H NMR (CDCl3, ppm) δ: 1.24 (t, 3H, J = 7.1 Hz,
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Zare et al.
321
Table 3 (concluded).
aIsolated yield.
bThis reaction was carried out at 100 °C because of the lower boiling point of ethyl acrylate.
cIn this reaction, both N9 and N7 isomers were produced.
CH2CH3), 1.88 (s, 3H, CH3), 2.75 (t, 2H, J = 6.0 Hz,
O=CCH2), 3.83 (t, 2H, J = 6.0 Hz, NCH2), 4.12 (q, 2H, J =
7.1 Hz, OCH2), 7.25 (s, 1H, H6 of thymine), 10.19 (s, 1H,
NH).
3H, J = 7.0 Hz, CH3), 2.79 (t, 2H, J = 5.8 Hz, O=CCH2),
3.82 (t, 2H, J = 5.8 Hz, NCH2), 4.12 (q, 2H, J = 7.0 Hz,
OCH2), 7.61 (s, 1H, H6 of 5-bromouracil), 10.27 (s, 1H,
NH).
Benzyl 3-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-
yl)propanoate (1f)
Ethyl 3-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-
yl)propanoate (1d)
Column chromathography on silica gel and eluting with
EtOAc–n-hexane (2:1) gave a pale yellow buff. Isolated
yield: 0.470 g (86%). IR (KBr, cm–1): 3157, 3069, 2962,
Column chromathography on silica gel and eluting with
EtOAc–n-hexane (2:1) gave a pale yellow solid. Isolated
yield: 0.417 g (91%); mp 123–125 °C (lit. (9g) value mp
1
1732, 1682, 1644. H NMR (CDCl3, ppm) δ: 2.73 (t, 2H,
1
124–126 °C). H NMR (CDCl3, ppm) δ: 1.22 (t, 3H, J =
J = 5.9 Hz, O=CCH2), 3.77 (t, 2H, J = 5.9 Hz, NCH2), 4.89
(s, 2H, OCH2), 5.56 (d, 1H, J = 7.9 Hz, H5 of uracil), 7.09–
7.23 (complex, 6H, H1–H5 of phenyl group and H6 of ura-
cil), 10.32 (br, 1H, NH). 13C NMR (CDCl3) δ: 37.6, 45.3,
66.5, 101.4, 127.9, 128.8, 129.7, 132.0, 144.8, 151.3, 163.3,
171.5. MS m/z: 274 [M+]. Anal. calcd. for C14H14N2O4: C
61.31, H 5.14, N 10.21; found: C 61.45, H 5.30, N 10.09.
7.1 Hz, CH3), 2.79 (t, 2H, J = 5.7 Hz, O=CCH2), 3.80 (t,
2H, J = 5.7 Hz, NCH2), 4.10 (q, 2H, J = 7.1 Hz, OCH2),
7.28 (s, 1H, J = 6.7 Hz, H6 of 5-fluorouracil), 10.25 (s, 1H,
NH).
Ethyl 3-(5-bromo-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-
yl)propanoate (1e)
Column chromathography on silica gel and eluting with
EtOAc–n-hexane (2:1) gave a pale yellow solid. Isolated
yield: 0.522 g (90%); mp 140–145 °C (dec.) [(lit. (9g) value
Phenethyl 3-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-
yl)propanoate (1g)
Column chromathography on silica gel and eluting with
EtOAc–n-hexane (2:1) gave a pale yellow buff. Isolated
1
mp 143–150 °C (dec.)]. H NMR (CDCl3, ppm) δ: 1.25 (t,
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Can. J. Chem. Vol. 86, 2008
yield: 0.483 g (84%). IR (KBr, cm–1): 3165, 3058, 2956,
1734, 1686, 1651. H NMR (CDCl3, ppm) δ: 2.71 (t, 2H,
Ethyl 3-(6-amino-9H-purin-9-yl)propanoate (2a)
1
Column chromathography on silica gel and eluting with
EtOAc–n-hexane (3:1) gave a colorless solid. Isolated yield:
0.328 g (70%); mp 165–167 (lit. (9b) value mp 165–167).
1H NMR (CDCl3, ppm) δ: 1.19 (t, 3H, J = 6.9 Hz, CH3),
2.95 (t, 2H, J = 5.9 Hz, O=CCH2), 4.12 (t, 2H, J = 6.9 Hz,
OCH2), 4.49 (t, 2H, J = 5.9 Hz, NCH2), 6.41 (s, 2H, NH2),
7.96 (s, 1H, H2 of adenine), 8.45 (s, 1H, H8 of adenine).
J = 5.8 Hz, O=CCH2), 2.86 (t, 2H, J = 7.0 Hz, PhCH2), 3.81
(t, 2H, J = 5.8 Hz, NCH2), 4.32 (t, 2H, J = 7.0 Hz, OCH2),
5.60 (d, 1H, J = 7.9 Hz, H5 of uracil), 7.11–7.25 (complex,
6H, H1–H5 of phenyl group and H6 of uracil), 10.26 (br, 1H,
NH). 13C NMR (CDCl3) δ: 34.7, 36.2, 46.4, 65.0, 102.1,
126.3, 128.1, 128.8, 131.9, 145.3, 151.0, 164.1, 170.3. MS
m/z: 288 [M+]. Anal. calcd. for C15H16N2O4: C 62.49,
H 5.59, N 9.72; found: C 62.40, H 5.72, N 9.87.
Butyl 3-(6-amino-9H-purin-9-yl)propanoate (2b)
Column chromathography on silica gel and eluting with
EtOAc–n-hexane (3:1) gave a colorless solid. Isolated yield:
0.390 g (74%); mp 135–137 °C (lit. (9b) value mp 134–
Ethyl 3-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-
methylpropanoate (1h)
1
136 °C). H NMR (CDCl3, ppm) δ: 0.93 (t, 3H, J = 6.7 Hz,
Column chromathography on silica gel and eluting with
EtOAc–n-hexane (2:1) gave a pale yellow oil (lit. (9b) oil).
Isolated yield: 0.219 g (48%).1H NMR (CDCl3, ppm) δ:
1.16–1.21 (complex, 6H, CH2CH3 and CHCH3), 2.95 (m,
1H, O=CCH), 3.64 (m, 1H, one H of NCH2), 3.82 (m, 1H,
one H of NCH2), 4.12 (q, 2H, J = 7.0 Hz, OCH2), 5.63 (d,
1H, J = 7.9 Hz, H5 of uracil), 7.22 (d, 1H, J = 7.9 Hz, H6 of
uracil), 10.22 (s, 1H, NH),
CH3), 1.36 (m, 2H, CH3CH2), 1.58 (m, 2H, CH3CH2CH2),
2.93 (t, 2H, J = 5.8 Hz, O=CCH2), 4.11 (t, 2H, J = 6.8 Hz,
OCH2), 4.53 (t, 2H, J = 5.8 Hz, NCH2), 6.38 (s, 2H, NH2),
7.99 (s, 1H, H2 of adenine), 8.40 (s, 1H, H8 of adenine).
Butyl 3-(6-(benzylamino)-9H-purin-9-yl)propanoate (2c)
Column chromathography on silica gel and eluting with
EtOAc–n-hexane (1:1) gave a dark yellow oil. Isolated yield:
1
0.626 g (89%). IR (KBr, cm–1): 3368, 3076, 2947, 1731. H
Ethyl 3-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-
yl)butanoate (1i)
NMR (CDCl3, ppm) δ: 0.89 (t, 3H, J = 6.8 Hz, CH3), 1.37
(m, 2H, CH3CH2), 1.55 (m, 2H, CH3CH2CH2), 2.96 (t, 2H,
J = 5.7 Hz, O=CCH2), 4.09 (t, 2H, J = 6.9 Hz, OCH2), 4.45
(t, 2H, J = 5.7 Hz, NCH2), 4.78 (s, 2H, PhCH2), 7.14–7.25
(complex, 6H, H1–H5 of the phenyl group and NH), 7.94 (s,
1H, H2 of purine nucleobase), 8.45 (s, 1H, H8 of purine
nucleobase). 13C NMR (62.5 MHz, CDCl3) δ: 13.9, 19.5,
30.9, 38.9, 45.2, 46.1, 65.2, 120.8, 127.3, 128.9, 129.6,
131.7, 139.2, 150.4, 151.9, 156.2, 171.9. MS m/z: 353 [M+].
Anal. calcd. for C19H23N5O2: C 64.57, H 6.56, N 19.82;
found: C 64.81, H 6.73, N 19.63.
Column chromathography on silica gel and eluting with
EtOAc–n-hexane (2:1) gave a pale yellow solid. Isolated
yield: 0.184 g (41%); mp 115–117 °C (lit. (9b) vaue mp
116–118 °C).1H NMR (CDCl3, ppm) δ: 1.22 (t, 3H, J =
7.0 Hz, CH2CH3), 1.39 (d, 3H, J = 6.9 Hz, CHCH3), 2.65
(m, 1H, one H of O=CCH2), 2.86 (m, 1H, one H of
O=CCH2), 4.11 (q, 2H, J = 7.0 Hz, OCH2), 4.65 (m, 1H,
CH3CH), 5.65 (d, 1H, J = 7.9 Hz, H5 of uracil), 7.25 (d, 1H,
J = 7.9 Hz, H6 of uracil), 10.24 (s, 1H, NH).
Butyl 3-(6-oxo-1,6-dihydropurin-9-yl)propanoate (2d)
Column chromathography on silica gel and eluting with
EtOAc–n-hexane (3:1) gave a colorless solid. Isolated yield:
0.389 g (74%); mp 83–85 °C. IR (KBr, cm–1): 3464, 3083,
Ethyl 2-methyl-3-(5-methyl-2,4-dioxo-3,4-
dihydropyrimidin-1(2H)-yl)propanoate (1j)
Column chromathography on silica gel and eluting with
EtOAc–n-hexane (2:1) gave a pale yellow solid. Isolated
yield: 0.215 g (45%); mp 40–42 °C. IR (KBr, cm–1): 3170,
1
2958, 1732, 1682. H NMR (CDCl3, ppm) δ: 0.92 (t, 3H,
J = 6.8 Hz, CH3), 1.35 (m, 2H, CH3CH2), 1.58 (m, 2H,
CH3CH2CH2), 2.87 (t, 2H, J = 5.8 Hz, O=CCH2), 4.12 (t,
2H, J = 6.9 Hz, OCH2), 4.52 (t, 2H, J = 5.8 Hz, NCH2), 7.99
(s, 1H, H8 of hypoxanthine), 8.56 (s, 1H, H2 of
hypoxanthine), 10.43 (s, 1H, NH). 13C NMR (62.5 MHz,
CDCl3) δ: 14.1, 19.3, 30.4, 39.6, 47.1, 65.4, 122.6, 151.8,
152.2, 152.9, 156.3, 171.3. MS m/z: 264 [M+]. Anal. calcd.
for C12H16N4O3: C 54.54, H 6.10, N 21.20; found: C 54.76,
H 5.94, N 21.38.
1
3072, 2969, 1732, 1685, 1641. H NMR (CDCl3, ppm) δ:
1.10–1.17 (complex, 6H, CHCH3 and CH2CH3), 1.95 (s, 3H,
CH3 of thymine), 2.94 (m, 1H, O=CCH), 3.61 (m, 1H, one
H of NCH2), 3.82 (m, 1H, one H of NCH2), 4.08 (q, 2H, J =
7.0 Hz, OCH2), 7.16 (s, 1H, H6 of thymine), 10.21 (br, 1H,
NH). 13C NMR (62.5 MHz, CDCl3): δ: 13.7, 14.5, 18.9,
39.8, 47.3, 64.7, 109.9, 140.6, 151.2, 164.9, 171.4. MS m/z:
240 [M+]. Anal. calcd. for C11H16N2O4: C 54.99, H 6.71, N
11.66; found: C 55.11, H 6.62, N 11.79.
Butyl 3-(6-oxo-1,6-dihydropurin-7-yl)propanoate (3d)
Column chromathography on silica gel and eluting with
EtOAc–n-hexane (3:1) gave a colorless solid. Isolated yield:
0.097 g (18%); mp 99–102 °C. IR (KBr, cm–1): 3429, 3071,
Ethyl 3-(4-acetamido-2-oxopyrimidin-1(2H)-
yl)propanoate (1k)
Column chromathography on silica gel and eluting with
EtOAc–n-hexane (2:1) gave a colorless solid. Isolated yield:
0.421 g (83%); mp 127–129 °C (lit. (9g) value mp 130–
1
2946, 1732, 1686. H NMR (CDCl3, ppm) δ: 0.90 (t, 3H,
J = 6.8 Hz, CH3), 1.38 (m, 2H, CH3CH2), 1.59 (m, 2H,
CH3CH2CH2), 2.90 (t, 2H, J = 5.9 Hz, O=CCH2), 4.08 (t,
2H, J = 6.8 Hz, OCH2), 4.74 (t, 2H, J = 5.9 Hz, NCH2), 8.10
(s, 1H, H8 of hypoxanthine), 8.64 (s, 1H, H2 of
hypoxanthine), 10.48 (s, 1H, NH).13C NMR (62.5 MHz,
CDCl3) δ: 13.9, 19.6, 31.6, 40.8, 50.8, 65.1, 118.9, 150.7,
1
131 °C). H NMR (CDCl3, ppm) δ: 1.21 (t, 3H, J = 7.0 Hz,
CH2CH3), 2.19 (s, 3H, O=CCH3), 2.82 (t, 2H, J = 5.8 Hz,
O=CCH2), 3.97 (t, 2H, J = 5.8 Hz, NCH2), 4.09 (t, 2H, J =
7.0 Hz, OCH2), 7.25 (d, 1H, J = 7.3 Hz), 7.73 (d, 1H, J =
7.3 Hz), 9.25 (s, 1H, NH).
© 2008 NRC Canada

Zare et al.
323
152.9, 153.2, 158.0, 171.9. MS m/z: 264 [M+]. Anal. calcd.
for C12H16N4O3: C 54.54, H 6.10, N 21.20; found: C 54.33,
H 6.36, N 21.35.
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1
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We appreciate Payame Nour University of Bushehr, Per-
sian Gulf University, and Shiraz University research councils
for financial support of this work.
© 2008 NRC Canada

324
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