Microwave-assisted Michael addition of some pyrimidine and purine nucleobases with α,β-unsaturated esters: A rapid entry into carboacyclic nucleoside synthesis

Article abstract of DOI:10.1055/s-2004-834950

An efficient procedure for the synthesis of some carboacyclic nucleosides via microwave-assisted Michael addition of various nucleobases to α,β-unsaturated esters in the presence of tetrabutylammonium bromide (TBAB) and DABCO is described. Using this method, some pyrimidine and purine nucleobases have been alkylated regioselectively in moderate to high yields and short reaction time. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2004-834950

PAPER
419
Microwave-Assisted Michael Addition of Some Pyrimidine and Purine
Nucleobases with a,b-Unsaturated Esters: A Rapid Entry into Carboacyclic
Nucleoside Synthesis
M
icrowave-Assist
.
e
d
Michael
A
K
dditionReactions
h
to
a
,
b
-Unsa
a
turated
E
ste
l
r
s
afi-Nezhad,* A. Zarea, M. N. Soltani Rad, B. Mokhtari, A. Parhami
Department of Chemistry, College of Science, Shiraz University, Shiraz 71454, Iran
Fax +98(711)2280926; E-mail: khalafi@chem.susc.ac.ir
Received 8 September 2004; revised 17 October 2004
Abstract: An efficient procedure for the synthesis of some carbo-
acyclic nucleosides via microwave-assisted Michael addition of
various nucleobases to a,b-unsaturated esters in the presence of
tetrabutylammonium bromide (TBAB) and DABCO is described.
Using this method, some pyrimidine and purine nucleobases have
been alkylated regioselectively in moderate to high yields and short
reaction time.
H
O
O
O
OH
Helenalin
Figure 1 Structure of helenalin
Key words: carboacyclic nucleosides, microwave, Michael addi-
tion, nucleobases, a,b-unsaturated esters
4h
acceptors. For example, NaOEt4a,d and K2CO3 catalyze
the Michael reaction of various Michael acceptors with
Microwave-assisted organic reactions have been used as pyrimidine and purine nucleobases. Catalysts, such as ba-
an effective technique in organic synthesis. Microwave ir- sic clay,9a transition metal complexes,9b–f lanthanides,9g
radiation often leads to large reduction in reaction time, proline,9h salen-Al complex,9i and enzyme4c have been
increased yields, easier workup, matches with green used to facilitate Michael additions. The conventional
chemistry protocols, and can enhance the regio- and ste- thermal methods for Michael additions of nucleobases to
reoselectivity of reactions.1,2a Furthermore, its unique ca- a,b-unsaturated esters are associated with several draw-
pabilities allow its application in reactions which are backs: (i) to dissolve the nucleobases in reaction media
difficult or impossible to carry out by means of customary the use of solvents such as DMF or DMSO is inevitable,
conventional methods.3 In fact, the high usefulness of mi- therefore, the workup of reaction is not only cumbersome
crowave-assisted synthesis, encouraged us to increase the but also the green aspect of reaction is annihilated by us-
efficiency of several organic transformations and synthe- ing DMF; (ii) long reaction times; and (iii) low reaction
sis.2
yields and selectivity. To overcome these drawbacks and
also in extension of our previous studies on application of
microwave technique in synthesis of some acyclic nucle-
oside analogs published in this journal,2f herein we report
a clean, facile, and rapid microwave-assisted regioselec-
tive Michael addition of some nucleobases to a,b-unsatur-
ated esters, which to the best of our knowledge has not
been reported so far.
The reaction of nucleobases with a,b-unsaturated esters is
significant as this reaction provide a direct and appealing
route into carboacyclic nucleoside synthesis.4 This class
of compounds has found particular interest for a variety of
biological studies.5 Moreover, it is demonstrated that
some a,b-unsaturated ketones as well as a,b-methylene
lactones could be served as alkylating agent useful in can-
cer therapy, as their reaction with electron-rich site of nu- To obtain optimized reaction conditions, we have selected
cleobases by conjugated addition (Michael addition) the reaction of uracil with ethyl acrylate as a model reac-
inhibits DNA replication in tumor cells.6 The naturally oc- tion to provide compound 1a (Scheme 1). For this pur-
curring sesquiterpene helenalin (Figure 1) is exemplified pose, the influence of various bases was examined to
to have conspicuous antitumor activities.7 Therefore, the evaluate their capabilities as well as their selectivity. The
reaction of nucleobases with a,b-unsaturated carbonyl results are summarized in Table 1. As Table 1 indicates,
compounds seems to be significant from the standpoint of higher yields and shorter reaction times were observed
medicinal chemistry.
when 1,4-diazabicyclo[2.2.2]octane (DABCO) was used
in the presence of a catalytic amount of tetrabutylammo-
nium bromide (TBAB). Therefore, DABCO was the base
of choice for our reactions. We have also extended this re-
action to adenine as a purine nucleobase that provided
compound 2a in high yield (Scheme 2).
Michael addition reactions have been used in the forma-
tion of carbon–oxygen,8a carbon–sulfur,8b and carbon–
carbon8c,d bonds. However, they normally require strong
bases or Lewis acids to activate nucleophiles or Michael
Interestingly, with our method both pyrimidine and purine
nucleobases were regioselectively alkylated. Pyrimidine
nucleobases were exclusively alkylated at N-1 position
SYNTHESIS 2005, No. 3, pp 0419–0424
Advanced online publication: 06.12.2004
DOI: 10.1055/s-2004-834950; Art ID: Z17004SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
5

420
A. Khalafi-Nezhad et al.
PAPER
O
N
O
To realize the capability of our method in comparison to
conventional methods, we have examined the synthesis of
compounds 1a and 1b (Scheme 1) with the method report-
ed by Cai et al.4c (Table 2). As Table 2 indicates, the mi-
crowave method is more efficient.
R1
R2
X
X
HN
R1
HN
O
DABCO/TBAB
microwave
200–300 W
6–10 min
+
CO2R3
O
N
H
R2
CO2R3
Table 2 A Comparative Synthesis of Compounds 1a and 1b Using
Conventional Thermal Versus Microwave Method
X = H, F, Me
1a–f
1
a
b
c
d
e
f
X
H
H
H
H
F
R1 R2 R3
H
H
H
H
H
Et
n-Bu
Product
1a
Time (h)a
Yield (%)a Time (min)b Yield (%)b
Me Et
12
12
47
44
6
6
83
85
Me H Et
H
Me H
H
H
Et
Et
1b
a Conventional thermal method.
b Microwave method.
Scheme 1
NH2
NH2
N
To study the structural influence of a,b-unsaturated esters
(Michael acceptors) on our reaction, we have also investi-
gated the reaction of uracil as well as adenine with more
sterically hindered ethyl methacrylate and ethyl crotonate
which afforded products 1c, 1d and 2c, 2d, respectively.
The results are depicted in Table 3. As shown in Table 3,
low yields of products were obtained when nucleobases
were introduced to sterically hindered a,b-unsaturated es-
ters (Table 3, entries 3,4,10,11). Prolonging the irradia-
tion times or exposing to higher microwave power has no
effect on the efficiency of reaction. Interestingly, the
length of alkoxy group (OR) in a,b-unsaturated esters has
negligible influence on the result of reaction. This can be
easily understood by comparing reaction yields of com-
pounds 1a, 1b and 2a, 2b accordingly (Table 3).
R1
R2
CO2R3
N
N
N
N
N
DABCO/TBAB
microwave
200–300 W
8–12 min
+
N
N
H
R2
R1
CO2R3
2a–d
R1 R2 R3
2
a
b
c
d
H
H
H
H
H
Et
n-Bu
Me Et
Me H Et
Scheme 2
Table 1 The Effect of Bases on Results of Michael Addition of
Uracil to Ethyl Acrylate
The reactions of uracil and adenine with ethyl cinnamate
were not successful (Table 3, entries 5, 12). This can be
attributed to the effect of the phenyl moiety, which can not
only deactivate a,b-ethylenic bonds owing to their conju-
gation, but its steric bulk can affect the progress of reac-
tion.
Entry
Base
Microwave Reaction
power (W) time (min)
Yield (%)a
1
2
3
4
5
6
7
DABCO
DMAP
Cs2CO3
K2CO3
DBU
200
200
200
200
200
300
300
6
8
83
70
65
59
52
41
18
TBAB has an undeniable effect on the progress of our re-
action. The absence of TBAB in the reaction media gave
low yields even by enhancing the reaction time and micro-
wave power. Thus, the presence of TBAB in our reaction
is critically significant. TBAB absorbs the microwave ir-
radiation as well as generates in situ heat and increases the
temperature higher than its melting point (100–103 °C).
In this conditions, TBAB creates homogeneous media
whose resemblance is not far from that of ionic liquids.2f,10
8
8
8
CaO
10
12
MgO
a Isolated yield.
In summary, we have developed an efficient, rapid, and
operationally simple method for regioselective Michael
additions of different nucleobases to various a,b-unsatur-
ated esters under microwave irradiation. This new method
affords carboacyclic nucleosides as biologically interest-
ing compounds in short reaction time and reasonable
yields.
and adenine was restrictively alkylated at N-9 rather than
N-7 position. The site of N-alkylation in both pyrimidine
and purine nucleobases were indicated by assigned 1H and
13C NMR spectra analysis. Several literatures also con-
firmed this site of N-alkylation.4c–e
Synthesis 2005, No. 3, 419–424 © Thieme Stuttgart · New York

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Microwave-Assisted Michael Addition Reactions to a,b-Unsaturated Esters
421
Table 3 Michael Addition Reactions of Some Nucleobases to a,b-Unsaturated Esters under Microwave Irradiation
Entry
1
Ester
Product
Microwave power (W)
200
Reaction time (min)
6
Yield (%)a
83
O
CO2Et
HN
O
N
CO2Et
2
3
4
200
200
300
6
10
9
85
40
27
O
N
CO2Bu
HN
O
O
O
CO2Bu
O
N
HN
CO2Et
CO2Et
O
N
CO2Et
HN
CO2Et
5b
6
–
400
200
10
6
–
Ph
CO2Et
81
O
N
CO2Et
CO2Et
CO2Et
F
HN
O
CO2Et
7
8
200
200
6
8
78
72
O
N
HN
O
N
CO2Et
NH2
N
N
N
CO2Et
Synthesis 2005, No. 3, 419–424 © Thieme Stuttgart · New York

422
A. Khalafi-Nezhad et al.
PAPER
Table 3 Michael Addition Reactions of Some Nucleobases to a,b-Unsaturated Esters under Microwave Irradiation (continued)
Entry
9
Ester
Product
Microwave power (W)
200
Reaction time (min)
8
Yield (%)a
73
NH2
CO2Bu
N
N
N
N
CO2Bu
10
11
200
300
400
12
10
10
38
24
–
NH2
N
N
N
CO2Et
N
CO2Et
NH2
N
N
N
N
CO2Et
CO2Et
12b
–
Ph
CO2Et
a Isolated yield.
b No reaction was observed.
All chemicals were obtained from Fluka or Merck. Solvents were
purified and dried according to reported methods and stored over
molecular sieves.11 The progress of reaction was followed by TLC
analysis using silica gel SILG/UV 254 plates . IR spectra were run
3-(2,4-Dioxo-3,4-dihydro-2H-pyrimidine-1-yl)propionic Acid
Ethyl Ester (1a)
Colorless crystals; yield: 1.76 g (83%); mp 78–80 °C (Lit.4c mp 79–
81 °C).
1
on a Shimadzu FTIR-8300 spectrophotometer. The H NMR and
13C NMR were run on a Bruker Avance DPX-250, FT-NMR spec-
trometer (d in ppm, J in Hz). Mass spectra were recorded on a Shi-
madzu GC MS-QP 1000 EX apparatus. Melting points were
recorded on a Büchi 510 apparatus in open capillary tubes and are
uncorrected. Microwave oven: MB 245 domestic microwave oven
from Butan Industrial Co.
3-(2,4-Dioxo-3,4-dihydro-2H-pyrimidine-1-yl)propionic Acid
Butyl Ester (1b)
Colorless crystals; yield: 2.03 g (85%); mp 63–65 °C; (Lit.4c mp 64–
66 °C).
3-(2,4-Dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-2-methylpropi-
onic Acid Ethyl Ester (1c)
Michael Addition of Nucleobases to a,b-Unsaturated Esters Un-
der Microwave Irradiation; General Procedure
Yellow oil; yield: 0.91 g (40%).
IR (neat): 3179, 3060, 2953, 1732s, 1686s, 1641s cm–1.
In a mortar, a mixture of compounds consisting of nucleobase
(0.010 mol), TBAB (0.644 g, 0.002 mol) and DABCO (1.120 g,
0.010 mol) was crushed vigorously to give a homogeneous mass.
The mixture was transferred into a test tube, and then the corre-
sponding a,b-unsaturated ester (0.015 mol) was added and mixed
carefully with a tiny spatula. The mixture was irradiated in the mi-
crowave oven at 200–300 W (Table 3) for several time intervals
(1.5 min). After each irradiation time interval, the microwave irra-
diation was stopped and the progress of the reaction was monitored
by TLC analysis. The irradiation was continued until no progress in
the reaction was observed, as indicated by TLC. The irradiation was
stopped and the reaction mixture was suspended in CHCl3 (300
mL). The CHCl3 was washed with H2O (2 × 200 mL) and dried
(MgSO4). The solvent was evaporated and the crude product was
purified by column chromatography on silica gel with EtOAc–hex-
ane (3:1).
1H NMR (250 MHz, CDCl3): d = 1.14–1.19 (m, 6 H, CH2CH3 and
CHCH3), 2.97 (m, 1 H, O=CCH), 3.67 (dd, 1 H, J = 9.5, 13.4 Hz,
NCH2), 3.87 (dd, 1 H, J = 4.5, 13.4 Hz, NCH2), 4.10 (q, 2 H, J = 6.9
Hz, OCH2), 5.61 (d, 1 H, J = 7.9 Hz, 5-H of uracil), 7.25 (d, 1 H,
J = 7.9 Hz, 6-H of uracil), 10.23 (s, 1 H, NH).
13C NMR (62.5 MHz, CDCl3): d = 14.44, 15.47, 39.01, 51.98,
61.48, 102.23, 145.01, 151.59, 164.81, 174.89.
MS: m/z (%) = 227 (M+ + 1, 8.7), 226 (M+, 15.6), 181 (20.8), 153
(14.9), 125 (26.1), 112 (13.3), 84 (100), 69 (47.9), 55 (17.8), 41
(38.2).
3-(2,4-Dioxo-3,4-dihydro-2H-pyrimidine-1-yl)butyric Acid
Ethyl Ester (1d)
Colorless crystals; yield: 0.61 g (27%); mp 116–118 °C.
IR (KBr): 3149, 3092, 2934, 1730s, 1686s, 1654 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.19 (t, 3 H, J = 7.0 Hz, CH2CH3),
1.43 (d, 3 H, J = 6.9 Hz, CHCH3), 2.63 (dd, 1 H, J = 5.8, 16.2,
Synthesis 2005, No. 3, 419–424 © Thieme Stuttgart · New York

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Microwave-Assisted Michael Addition Reactions to a,b-Unsaturated Esters
423
O=CCH2), 2.85 (dd, 1 H, J = 7.9, 16.2, O=CCH2), 4.07 (q, 2 H,
J = 7.0 Hz, OCH2), 4.68 (m, 1 H, CH3CH), 5.67 (d, 1 H, J = 7.9 Hz,
5-H of uracil), 7.23 (d, 1 H, J = 7.9 Hz, 6-H of uracil), 9.70 (s, 1 H,
NH).
13C NMR (62.5 MHz, CDCl3): d = 14.47, 19.21, 39.32, 51.66,
61.40, 102.49, 142.77, 151.18, 164.06, 170.64.
13C NMR (62.5 MHz, CDCl3): d = 14.29, 20.44, 40.43, 49.18,
61.15, 120.38, 139.71, 149.88, 152.85, 156.40, 170.53.
MS: m/z (%) = 250 (M+ + 1, 85.8), 249 (M+, 36.7), 204 (12.7), 176
(16.9), 162 (30.6), 135 (100), 108 (34.7), 93 (3.2), 69 (16.4), 55
(8.6), 41 (30.1).
MS: m/z (%) = 227 (M+ + 1, 31.4), 226 (M+, 22.5), 181 (23.3), 153
(18.8), 152 (61.2), 139 (23.7), 112 (14.4), 96 (100), 69 (85.3), 41
(77.1).
Acknowledgment
We thank the Shiraz University research council for financial sup-
port of this work. We are also grateful to Mr. H. Sajedian Fard for
running the NMR spectra.
3-(5-Fluoro-2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)propi-
onic Acid Ethyl Ester (1e)
Pale yellow crystals; yield: 1.86 g (81%); mp 122–124 °C (Lit.4c mp
124–126 °C).
References
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3-(5-Methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)propi-
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Colorless crystals; yield: 1.76 g (78%); mp 148–149 °C (Lit.4c mp
149–150 °C).
3-(6-Aminopurine-9-yl)propionic Acid Ethyl Ester (2a)
Colorless crystals; yield: 1.69 g (72%); mp 165–167 °C (Lit.4a mp
167–168 °C).
3-(6-Aminopurine-9-yl)propionic Acid Butyl Ester (2b)
Colorless crystals; yield: 1.92 g (73%); mp 134–136 °C.
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IR (KBr): 3265, 3110, 2932, 1728s cm–1.
1H NMR (250 MHz, CDCl3): d = 0.92 (t, 3 H, J = 6.7 Hz, CH3),
1.34 (m, 2 H, CH3CH2), 1.55 (m, 2 H, CH3CH2CH2), 2.96 (t, 2 H,
J = 5.8 Hz, O=CCH2), 4.09 (t, 2 H, J = 6.7 Hz, OCH2), 4.53 (t, 2 H,
J = 5.8 Hz, NCH2), 6.37 (s, 2 H, NH2), 7.99 (s, 1 H, 2-H of adenine),
8.42 (s, 1 H, 8-H of adenine).
13C NMR (62.5 MHz, CDCl3): d = 14.32, 19.38, 30.96, 39.85,
46.44, 65.41, 121.67, 138.47, 150.24, 152.78, 156.11, 171.41.
MS: m/z (%) = 264 (M+ + 1, 20.4), 263 (M+, 22), 234 (4.1), 221
(8.2), 206 (2.1), 190 (14.3), 162 (77.6), 148 (32.7), 135 (100), 108
(24.5), 93 (5.1), 73 (4.1), 57 (9.2), 41 (36.7).
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3-(6-Aminopurine-9-yl)-2-methylpropionic Acid Ethyl Ester
(2c)
Colorless crystals; yield: 0.95 g (38%); mp 134–137 °C.
IR (KBr): 3511, 3296, 3139, 2930, 1728s cm–1.
1H NMR (250 MHz, CDCl3): d = 1.09–1.20 (m, 6 H, CH2CH3 and
CHCH3), 3.10 (m, 1 H, O=CCH), 4.04 (q, 2 H, J = 6.6 Hz, OCH2),
4.20 (dd, 1 H, J = 8.3, 13.9 Hz, NCH2), 4.38 (dd, 1 H, J = 8.6, 13.9
Hz, NCH2), 6.19 (s, 2 H, NH2), 7.77 (s, 1 H, 2-H of adenine), 8.28
(s, 1 H, 8-H of adenine).
13C NMR (62.5 MHz, CDCl3): d = 14.37, 15.49, 39.05, 46.35,
61.42, 119.76, 141.45, 150.34, 153.22, 156.17, 174.45.
MS: m/z (%) = 250 (M+ + 1, 12.3), 249 (M+, 18.1), 204 (17.3), 176
(40.8), 149 (85.7), 148 (58.2), 135 (100), 108 (38.8), 93 (6.3), 77
(5.5), 70 (38.7), 55 (46.9), 41 (85.7).
3-(6-Aminopurine-9-yl)butyric Acid Ethyl Ester (2d)
Colorless crystals; yield: 0.59 g (24%); mp 100–101 °C.
IR (KBr): 3335, 3142, 2928, 1729s cm–1.
1H NMR (250 MHz, CDCl3): d = 1.09 (t, 3 H, J = 6.3 Hz, CH2CH3),
1.66 (d, 3 H, J = 4.7 Hz, NCHCH3), 2.87 (dd, 1 H, J = 4.7, 16.8 Hz,
O=CCH2), 3.14 (dd, 1 H, J = 7.9, 16.8 Hz, O=CCH2), 4.02 (q, 2 H,
J = 6.3 Hz, OCH2), 4.95 (m, 1 H, NCHCH3), 6.26 (s, 2 H, NH2),
7.78 (s, 1 H, 2-H of adenine), 8.21 (s, 1 H, 8-H of adenine).
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