A fast and highly efficient protocol for Michael addition of N-heterocycles to α,β-unsaturated compound using basic ionic liquid [bmIm]OH as catalyst and green solvent

Article abstract of DOI:10.1016/j.tet.2006.11.013

A fast and green protocol for the Michael addition of N-heterocycles to α,β-unsaturated compounds at room temperature was developed using a basic ionic liquid, 1-methyl-3-butylimidazolium hydroxide, [bmIm]OH, as a catalyst and a reaction medium. The react

Full text of DOI:10.1016/j.tet.2006.11.013

Tetrahedron 63 (2007) 986–990
A fast and highly efficient protocol for Michael addition
of N-heterocycles to a,b-unsaturated compound using basic
ionic liquid [bmIm]OH as catalyst and green solvent
*
Jian-Ming Xu, Chao Qian, Bo-Kai Liu, Qi Wu and Xian-Fu Lin
Department of Chemistry, Zhejiang University, Hangzhou 310027, People’s Republic of China
Received 6 August 2006; revised 1 November 2006; accepted 3 November 2006
Available online 30 November 2006
Abstract—A fast and green protocol for the Michael addition of N-heterocycles to a,b-unsaturated compounds at room temperature was de-
veloped using a basic ionic liquid, 1-methyl-3-butylimidazolium hydroxide, [bmIm]OH, as a catalyst and a reaction medium. The reactions
were performed at room temperature with good yields in short reaction times (0.5–3 h). This strategy is quite general and it works with a broad
range of N-heterocycles, including five-membered N-heterocycles, pyrimidines and purines. The recovered ionic liquid could be reused for
several cycles with consistent activity.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Room temperature ionic liquids (RTLs) containing imidazo-
lium cations can act as a powerful medium in some organic
reactions to accelerate the reaction.8 RTLs include acidic,
neutral and basic ionic liquids. The acidic9 and neutral ionic
liquids10 have been well recognized and successfully applied
in many organic reactions. However, the related report about
the basic ionic liquids was rare. Supported choline hydrox-
ide was used as a catalyst for aldol condensation reactions
between several ketones and aldehydes.11 A basic ionic liq-
uid [bmIm]OH has been successfully applied to catalyze the
Michael addition of active methylene compounds to conju-
gated ketones, carboxylic esters and nitriles.12 We also
found that [bmIm]OH could be used as an efficient catalyst
for the Markovnikov addition of N-heterocycles and vinyl
esters.13 As a part of our study on environmentally friendly
organic synthesis with ionic liquid,13,14 we have accom-
plished, for the first time, the use of [bmIm]OH as a novel
and a recyclable reaction medium, as well as an efficient
catalyst for the Michael addition of N-heterocycles and
a,b-unsaturated compounds to generate the corresponding
1,4-aducts in high yields at room temperature (Scheme 1).
Some control experiments were also carried out to under-
stand the catalytic property of [bmIm]OH.
In recent years, there has been a growing interest in the syn-
thesis of biologically interesting compounds in the field of
organic chemistry. N-Substituted imidazoles, triazoles, pyr-
azoles, pyrimidines, purines and their derivatives obtained
through Michael addition are usually pharmacologically
active and may be applied as potential therapeutic alterna-
tives.1 Generally these reactions require strong bases or
Lewis acids to activate nucleophiles or Michael acceptors.
These would lead to environmentally hazardous residues
and undesirable side-products.2 To avoid typical disadvan-
tages resulting from the presence of such a catalyst, a large
number of alternative strategies have been developed in
the past few years using basic clays,3 KF/Al2O3,4 guani-
dine,5 microwave irradiation6 and enzyme.7 Unfortunately,
many of these procedures require long reaction times (sev-
eral days), rigorous reaction conditions or highly dangerous
chemicals. Moreover, the use of solvents such as DMSO or
DMF is inevitable for some N-heterocycles such as pyrimi-
dines and purines. Generally the catalyst could not be re-
cycled. Thus, development of a fast and facile protocol
that could be performed at ambient temperature for the
Michael addition of N-heterocycles to a,b-unsaturated com-
pounds becomes particularly fascinating and remains a great
challenge.
R'
Nu
R
EWG
R
[bmIm]OH
r.t.
+
Nu-H
R'
EWG
EWG=CN, CO2CH3, COCH3
Keywords: Ionic liquid; Michael addition; N-Heterocycle; a,b-Unsaturated
compounds.
* Corresponding author. Fax: +86 571 87952618; e-mail: llc123@zju.edu.cn
Scheme 1. Michael addition of N-heterocycles to a,b-carbonyl compound
promoted by [bmIm]OH.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.11.013

J.-M. Xu et al. / Tetrahedron 63 (2007) 986–990
987
Table 1. Michael addition of imidazoles to vinyl esters promoted by
2. Results and discussion
[bmIm]OHa
The ionic liquid [bmIm]OH was synthesized according to
the procedure reported in the literature.12 Reactions were
typically carried out by addition of methyl acrylate
(1.5 mmol) to the ionic liquid (1 mL) containing 4-nitro-
imidazole (1.0 mol). Generally, after 1–2 h, the reaction so-
lution turned pellucid, indicating the end of the reaction. The
adduct was extracted with ethyl acetate and purified by flash
chromatography. The structure of this compound was con-
firmed by IR, 1H NMR, 13C NMR and ESI-MS. The residual
ionic liquid was washed with ethyl ether, dried under vac-
uum at 90 ꢀC for 2 h to eliminate any water trapped from
moisture and reused for subsequent reactions. The recovered
ionic liquid could be used for four runs with 91%, 96%, 90%
and 92% yields. After five runs, about 50% fresh ionic liquid
was added to maintain consistent activity due to the loss of
ionic liquid.
Entry
1
Imidazole
a,b-Carbonyl compound Time (h) Yieldb (%)
NO2
N
1
(3a) 95
(3b) 96
(3c) 92
(3d) 90
(3e) 92
(3f) 96
(3g) 92
(3h) 88
(3i) 94
(3j) 80
(3k) 85
(3l) 60
(3m) 65
CO2Me
CO2Et
CO2But
CN
N
H
NO2
N
2
1.5
3
N
H
NO2
N
3
N
H
NO2
N
4
1
N
H
NO2
N
5
0.5
0.5
1
A variety of structurally diverse imidazoles and a,b-unsatu-
rated carbonyl compounds underwent Michael additions
smoothly without any other catalyst to generate the corre-
sponding imidazole derivatives in moderate to good yields.
The results are summarized in Table 1. Generally, the reac-
tivity decreased with increasing chain length of acceptor, the
longer chain the acrylates had, the lower reactivity was
observed (entries 1–3, Table 1). Apart from acrylate ester,
acrylonitrile and methyl vinyl acetone can also be the
substrates of this reaction to afford the desired products in
good yields and in short reaction times (entries 4, 5 and 7,
Table 1). Vinyl acrylate showed higher reactivity than methyl
acrylate (entry 6, Table 1). We have found that [bmIm]OH
could also catalyze the Markovnikov addition of N-hetero-
cycles and vinyl ester.13 In the reaction of 4-nitroimidazole
with vinyl acrylate, it is worthwhile to note that no Markov-
nikov adduct was detected by TLC and HPLC under the
current conditions. The Michael addition was much more
favoured than Markovnikov addition. Because vinyl acrylate
was excess in the reaction, only Michael adduct was
obtained.
O
O
N
H
NO2
N
6
O
N
H
N
7
CO2Me
CN
N
H
N
8
1
N
H
NO2
N
9
3
CO2Me
CO2Me
CO2Me
N
H
N
10
11
12c
2
N
H
N
1
N
H
In order to extend the scope of this methodology, a,b-
substituted Michael acceptors like methyl methacrylate
and methyl crotonate were tested under the same conditions
(entries 12 and 13, Table 1). Both of the acceptors showed
rather lower reactivity because of the strong steric hindrance.
Accordingly, higher temperature (50 ꢀC) and longer reaction
times were required. Similar results were observed using
imidazole as the nucleophile (entries 7 and 8, Table 1).
The four substituted imidazoles examined underwent
Michael addition with methyl acrylate favourably and all
substituted imidazoles could be obtained in good yields in
short reaction times (entries 1, 7, 9–11, Table 1). The re-
activity was in accordance with the nucleophilicity of imida-
zole derivatives. Sterically hindered imidazole underwent
Michael addition much more slowly (entry 10, Table 1).
NO2
N
N
6
CO2Me
N
H
NO2
13c
6
CO2Me
N
H
a
Reactions were carried out on 1.0 mmol scale of substrate with 1.5 equiv
of vinyl ester in 1 mL ionic liquid at 25 ꢀC.
Isolated yields.
Reaction was performed at 50 ꢀC.
b
c
such as pyrimidines and purines, also can be used as nucleo-
philes to obtain the corresponding Michael adducts in high
yields. Among the substituted pyrimidines, fluorouracil re-
acted faster than uracil and thymine. It is worthwhile to men-
tion that at room temperature (25 ꢀC) only N-1 adducts were
prepared (also monitored by TLC and HPLC). When the re-
action was carried out at 25 ꢀC under the catalysis of sodium
Having obtained favourable results with imidazoles, we then
examined the addition of other N-heterocycles to methyl ac-
rylate. Other five-membered N-heterocycles such as pyra-
zole and triazole also exhibited high reactivity (entries 1
and 2, Table 2). Among them, triazole reacted faster due to
its strong nucleophilicity. More complicated N-heterocycles,

988
J.-M. Xu et al. / Tetrahedron 63 (2007) 986–990
Table 2. Michael addition of other N-heterocycles with methyl acrylate
speculated that the catalysis of basic ionic liquid [bmIm]OH
may be attributed to the following reasons. First, N-hetero-
cycles exhibited higher nucleophilicity in ionic liquids com-
pared to the nucleophilicity in organic solvents.16 Second,
hydroxide anion of the ionic liquid [bmIm]OH could assist
in the formation of nucleophilic anions, which increased
the nucleophilicity of N-heterocycles further.
promoted by [bmIm]OHa
Entry
1
Substrate
Product
Time (h) Yieldb (%)
O
N
NH
N
1
1
(5a) 95
(5b) 85
N
N
OCH3
OCH3
N
N
O
N
NH
N
2
3
4
5
3. Conclusion
O
In summary, we have developed a procedure using a basic
ionic liquid [bmIm]OH to provide an efficient and conve-
nient protocol for Michael addition of N-heterocycles to
a,b-carbonyl compounds without requirement of a conven-
tional catalyst and organic solvent. The reactions have
been carried out at room temperature to afford the desired
products in good yields in short reaction times. This strategy
is quite general and it works with a broad range of N-hetero-
cycles, including five-membered N-heterocycles, pyrimi-
dines and purines. The obtained N-heterocycle derivatives
may be potentially pharmacological alternatives. The com-
plete study of the biological activity of these new derivatives
will be reported in due course.
O
F
F
HN
HN
1
2
2
(5c) 94
(5e) 94
(5f) 89
O
O
O
N
N
H
OCH3
OCH3
OCH3
O
O
HN
HN
O
O
O
O
N
O
N
H
O
CH3
HN
HN
O
O
N
N
H
4. Experimental
4.1. General
NHCH2Ph
N
NHCH2Ph
N
N
N
6
2
(5g) 90
O
N
N
N
H
1H and 13C NMR spectra were recorded on Bruker AVANCE
DMX-500 spectrometer at 500 MHz and 125 MHz in CDCl3
and DMSO-d6, respectively. Chemical shifts are reported in
parts per million (d), relative to the internal standard of
tetramethylsilane (TMS). IR spectra were measured with
a Nicolet Nexus FTIR 670 spectrophotometer. Mass spec-
trometry data were obtained on Brucker Esquire-LC for
electro-spray (MS-ES) measurements (solvents: methanol;
postitive mode). Melting points were determined using
XT-4 apparatus and were not corrected. All chemicals
were obtained from commercial suppliers and used without
further purification.
N
OCH3
a
Reactions were carried out on 1.0 mmol scale of substrate with 1.5 equiv
of methyl acrylate in 1 mL ionic liquid at 25 ꢀC.
Isolated yields.
b
hydroxide in DMF, however, N-1 and N-3 bis-alkylated ad-
duct was generated as the main product. This result revealed
that ionic liquid [bmIm]OH exhibited higher regioselectivity
relative to some solid bases such as sodium hydroxide.
Some control experiments were also carried out to demon-
strate the catalysis of [bmIm]OH. When the reaction was
carried out in some common organic solvents such as THF
and DMSO in the absence of [bmIm]OH, it was observed
that the addition reaction of 4-nitroimidazole to methyl acryl-
ate produced the corresponding product in less than 5%
yield in 48 h. On the other hand, the ionic liquid remained
intact (1H NMR) and was used for subsequent runs with-
out any difficulty. These results revealed that ionic liquid
[bmIm]OH played a significant role as a catalyst as well as
a reaction medium during the reaction process. It has been
reported that acidic C2-H of ionic liquids could interact
with the carbonyl group and influence the reaction results.15
We designed ionic liquid 1-butyl-2,3-dimethylimidazolium
hydroxide ([bdmIm]OH) in order to understand the role
of acidic C2-H in the Michael addition reaction. When
[bdmIm]OH was used to catalyze the Michael addition of
4-nitroimidazole with methyl acrylate, 93% isolated yield
was obtained in 60 min. This result was comparable with
that in [bmIm]OH, indicating that acidic C2-H of [bmIm]OH
did not play a significant role in the catalysis. Thus, we
4.2. Typical procedure
N-Heterocycles (1 mmol) and a,b-unsaturated carbonyl
compounds (1.5 mmol) were added to a 10 mL conical flask
containing 1 mL [bmIm]OH and the mixture was shaken at
ambient temperature for a period of time. The reaction mix-
ture was extracted from the ionic liquid phase with ethyl
acetate (10.0 mLꢁ3). The organic layer was dried over
anhydrous sodium sulfate and evaporated under reduced
pressure. The residue was purified by flash column chroma-
tography (silica gel, petroleum ether/ethyl acetate¼1/2, v/v)
to obtain the corresponding Michael adduct. The ionic liquid
left in the conical flask was further washed with ether, dried
under vacuum at 90 ꢀC for 2 h to eliminate any water trapped
from moisture and reused for subsequent reactions. After
five runs, about 50% fresh ionic liquid was added to maintain
consistent activity.
4.2.1. 3-(4-Nitroimidazol-1-yl)-propionic acid methyl
ester (3a). White solid, mp 109 ꢀC; IR (KBr): 1729, 1526,

J.-M. Xu et al. / Tetrahedron 63 (2007) 986–990
989
1485 cmꢂ1; 1H NMR (CDCl3, d, ppm): 7.83 (s, 1H), 7.51 (s,
1H), 4.35 (t, 2H, J¼6.1 Hz), 3.73 (s, 3H), 2.86 (t, 2H,
J¼6.1 Hz); 13C NMR (CDCl3, d, ppm): 170.5, 148.9,
136.6, 119.7, 52.7, 43.8, 35.3; ESI-MS (m/z): 200 (M+1).
147.8, 123.1, 54.7, 45.0, 36.9, 15.5; ESI-MS (m/z): 214
(M+1).
4.2.10. 3-(2-Methyl-imidazol-1-yl)-propionic acid methyl
ester (3j). Yellow oil; IR (neat): 1733, 1508 cmꢂ1; 1H NMR
(CDCl3, d, ppm): 6.90 (s, 1H), 6.84 (s, 1H), 4.16 (t, 2H,
J¼6.8 Hz), 3.69 (s, 3H), 2.74 (t, 2H, J¼6.8 Hz), 2.41 (s,
3H); 13C NMR (CDCl3, d, ppm): 170.6, 144.1, 126.8,
118.6, 51.6, 41.0, 34.8, 12.4; ESI-MS (m/z): 183 (M+1).
4.2.2. 3-(4-Nitroimidazol-1-yl)-propionic acid ethyl ester
(3b). White solid, mp 35–37 ꢀC; IR (KBr): 1733, 1519,
1
1492 cmꢂ1; H NMR (CDCl3, d, ppm): 7.85 (s, 1H), 7.51
(s, 1H), 4.36 (t, 2H, J¼6.1 Hz), 4.18 (q, 2H, J¼7.1 Hz),
2.85 (t, 2H, J¼6.1 Hz), 1.25 (t, 3H, J¼7.1 Hz); 13C NMR
(CDCl3, d, ppm): 170.2, 148.9, 136.6, 119.7, 61.9, 43.8,
35.5, 14.3; ESI-MS (m/z): 214 (M+1).
4.2.11. 3-(4-Methyl-imidazol-1-yl)-propionic acid methyl
ester (3k). Yellow oil; IR (neat): 1732, 1508 cmꢂ1; 1H NMR
(CDCl3, d, ppm): 7.44 (s, 0.4H), 7.38 (s, 0.6H), 6.75 (s,
0.4H), 6.62 (s, 0.6H), 4.18–4.15 (m, 2H), 3.69 (s, 3H),
2.76–2.74 (m, 2H), 2.21 (d, 3H); 13C NMR (CDCl3, d,
ppm): 171.2, 171.0, 138.6, 136.9, 136.4, 126.9, 115.4,
52.1, 42.3, 40.0, 35.8, 35.3, 13.6, 9.1; ESI-MS (m/z): 183
(M+1).
4.2.3. 3-(4-Nitroimidazol-1-yl)-propionic acid butyl ester
(3c). White solid, mp 48 ꢀC; IR (KBr): 1727, 1521,
1
1488 cmꢂ1; H NMR (CDCl3, d, ppm): 7.84 (s, 1H), 7.51
(s, 1H), 4.36 (t, 2H, J¼6.1 Hz), 4.12 (t, 2H), 2.86 (t, 2H,
J¼6.1 Hz), 1.63–1.57 (m, 2H), 1.36–1.32 (m, 2H), 0.94 (t,
3H); 13C NMR (CDCl3, d, ppm): 170.3, 148.9, 136.6,
119.6, 65.7, 43.8, 35.5, 30.7, 19.2, 13.8; ESI-MS (m/z):
242 (M+1).
4.2.12. 2-Methyl-3-(4-nitroimidazol-1-yl)-propionic acid
methyl ester (3l). White solid, mp 64–65 ꢀC; IR (KBr):
1
1726, 1527, 1485 cmꢂ1; H NMR (CDCl3, d, ppm): 7.8 (s,
4.2.4. 3-(4-Nitroimidazol-1-yl)-propionitrile (3d). White
1H), 7.46 (s, 1H), 4.34–4.30, 4.16–4.12 (m, 2H), 3.71 (s,
3H), 2.97–2.94 (m, 1H), 1.28 (d, 3H); 13C NMR (CDCl3,
d, ppm): 173.7, 148.4, 136.8, 119.9, 52.7, 50.4, 41.2, 15.2;
ESI-MS (m/z): 214 (M+1).
solid, mp 105–106 ꢀC; IR (KBr): 2252, 1526, 1492 cmꢂ1
;
1H NMR (DMSO-d6, d, ppm): 8.47 (s, 1H), 7.93 (s, 1H),
4.38 (t, 2H, J¼6.3 Hz), 3.17 (t, 2H, J¼6.3 Hz); 13C NMR
(DMSO-d6, d, ppm): 147.6, 138.1, 121.9, 118.6, 43.5,
19.4; ESI-MS (m/z): 167 (M+1).
4.2.13. 3-(4-Nitroimidazol-1-yl)-butyric acid methyl ester
(3m). White solid, mp 113–114 ꢀC; IR (KBr): 1734, 1543,
1
4.2.5. 4-(4-Nitroimidazol-1-yl)-butanone (3e). Yellow
1489 cmꢂ1; H NMR (CDCl3, d, ppm): 7.85 (s, 1H), 7.55
1
solid, mp 65–67 ꢀC; IR (KBr): 1741, 1523, 1490 cmꢂ1; H
(s, 1H), 4.81–4.77 (m, 1H), 3.68 (s, 3H), 2.84 (d, 2H), 1.64
(d, 3H); 13C NMR (CDCl3, d, ppm): 170.0, 148.7, 135.4,
117.5, 52.5, 51.8, 42.0, 21.5; ESI-MS (m/z): 214 (M+1).
NMR (CDCl3, d, ppm): 7.82 (d, 1H, J¼1.46 Hz), 7.49 (d,
1H, J¼1.42 Hz), 4.32 (t, 2H, J¼5.92 Hz), 3.02 (t, 2H,
J¼5.92 Hz), 2.21 (s, 3H,); 13C NMR (CDCl3, d, ppm):
204.3, 148.1, 136.8, 120.1, 43.8, 42.4, 30.2; ESI-MS (m/z):
184 (M+1).
4.2.14. 3-[1,2,4]Triazol-1-yl-propionic acid methyl ester
1
(5a). Yellow oil; IR (neat): 1735, 1507, 1440 cmꢂ1; H
NMR (CDCl3, d, ppm): 8.17 (s, 1H), 7.93 (s, 1H), 4.49 (t,
2H, J¼6.3 Hz), 3.69 (s, 3H), 2.93 (t, 2H, J¼6.3 Hz); 13C
NMR (CDCl3, d, ppm): 171.0, 152.2, 143.8, 52.2, 44.9,
34.0; ESI-MS (m/z): 156 (M+1).
4.2.6. 3-(4-Nitroimidazol-1-yl)-propionic acid vinyl ester
(3f). White solid, mp 94–96 ꢀC; IR (KBr): 1743, 1649, 1526,
1486 cmꢂ1; 1H NMR (CDCl3, d, ppm): 7.88 (s, 1H), 7.54 (s,
1H), 7.26–7.22 (m, 1H), 4.95–4.91, 4.67 (m, 2H), 4.41 (t,
2H, J¼6.1 Hz), 2.98 (t, 2H, J¼6.1 Hz); 13C NMR (CDCl3,
d, ppm): 167.6, 148.9, 140.8, 136.7, 119.8, 99.4, 43.4,
35.1; ESI-MS (m/z): 212 (M+1).
4.2.15. 3-Pyrazol-1-yl-propionic acid methyl ester (5b).
1
Yellow oil; IR (neat), 1739, 1514, 1439 cmꢂ1; H NMR
(CDCl3, d, ppm): 7.50 (d, 1H), 7.43 (d, 1H), 6.21 (t, 1H),
4.43 (t, 2H, J¼6.6 Hz), 3.67 (s, 3H), 2.90 (t, 2H,
J¼6.6 Hz); 13C NMR (CDCl3, d, ppm): 171.6, 139.8,
129.8, 105.5, 52.0, 47.4, 34.9; ESI-MS (m/z): 155 (M+1).
4.2.7. 3-Imidazol-1-yl-propionic acid methyl ester (3g).
1
Yellow oil; IR (neat): 1732, 1509 cmꢂ1; H NMR (CDCl3,
d, ppm): 7.54 (s, 1H), 7.05 (s, 1H), 6.93 (s, 1H), 4.27 (t,
2H, J¼6.6 Hz), 3.70 (s, 3H), 2.78 (t, 2H, J¼6.6 Hz); 13C
NMR (CDCl3, d, ppm): 170.3, 136.6, 128.5, 118.2, 51.1,
41.5, 34.9; ESI-MS (m/z): 155 (M+1).
4.2.16. 3-(5-Fluorouracil-1-yl)-propionic acid methyl
ester (5c). Yellow solid, mp 145–146 ꢀC; IR (KBr): 1729,
1
1692, 1663 cmꢂ1; H NMR (CDCl3, d, ppm): 7.52 (s, 1H),
3.97 (t, 2H, J¼5.8 Hz), 3.72 (s, 3H, O–CH3), 2.79 (t, 2H,
J¼5.8 Hz); 13C NMR (CDCl3, d, ppm): 172.0, 157.5,
157.3, 149.6, 141.2, 139.2, 130.5, 130.3, 52.5, 45.8, 32.9;
ESI-MS (m/z): 217 (M+1).
4.2.8. 3-Imidazol-1-yl-propionitrile (3h). Yellow oil; IR
1
(neat): 2253, 1509 cmꢂ1; H NMR (CDCl3, d, ppm): 7.56
(s, 1H), 7.07 (s, 1H), 7.03 (s, 1H), 4.24 (t, 2H, J¼6.5 Hz),
2.82 (t, 2H, J¼6.5 Hz); 13C NMR (CDCl3, d, ppm): 137.1,
130.5, 118.8, 116.7, 42.7, 20.8; ESI-MS (m/z): 122 (M+1).
4.2.17. 3-Uracil-1-yl-propionic acid methyl ester (5d).
White solid, mp 127–128 ꢀC; IR (KBr): 1733, 1696,
4.2.9. 3-(2-Methyl-4-nitroimidazol-1-yl)-propionic acid
methyl ester (3i). Yellow liquid; IR (neat): 1729,
1662 cmꢂ1 1H NMR (CDCl3, d, ppm): 2.80 (t, 3H,
;
J¼5.9 Hz), 3.71 (s, 3H), 4.00 (t, 2H, J¼5.9 Hz), 5.68 (d,
1H, J¼7.9 Hz), 7.40 (d, 1H, J¼7.9 Hz), 9.03 (s, 1H); 13C
NMR (CDCl3, d, ppm): 172.1, 164.0, 151.0, 146.0, 102.0,
52.4, 45.5, 33.0; ESI-MS (m/z): 199 (M+1).
1
1508 cmꢂ1; H NMR (CDCl3, d, ppm): 7.76 (s, 1H), 4.25
(t, 2H, J¼6.4 Hz), 3.72 (s, 3H), 2.82 (t, 2H, J¼6.4 Hz),
2.48 (s, 3H); 13C NMR (CDCl3, d, ppm): 173.2, 148.9,

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J.-M. Xu et al. / Tetrahedron 63 (2007) 986–990
3. Martin-Aranda, R. M.; Ortega-Cantero, E.; Rojas-Cervantes,
M. L.; Vicente-Rodriguez, M. A.; Banares-Munoz, M. A.
Catal. Lett. 2002, 84, 201–204.
4.2.18. 3-Thymin-1-yl-propionic acid methyl ester (5e).
White solid, mp 120–121 ꢀC; IR (KBr): 1735, 1698,
1
1655 cmꢂ1; H NMR (CDCl3, d, ppm): 8.87 (s, 1H), 7.20
4. Yang, L.; Xu, L. W.; Xia, C. G. Tetrahedron Lett. 2005, 46,
3279–3282.
5. Horvath, A. Tetrahedron Lett. 1996, 37, 4423–4426.
6. Leadbeater, N. E.; Pillsbury, S. J.; Shanahan, E.; Williams,
V. A. Tetrahedron 2005, 61, 3565–3585.
(s, 1H), 3.96 (t, 2H, J¼6.0 Hz), 3.71 (s, 3H), 2.78 (t, 2H,
J¼6.0 Hz), 1.91 (s, 3H); 13C NMR (CDCl3, d, ppm):
172.1, 164.6, 151.1, 141.8, 110.6, 52.3, 45.3, 33.1, 12.5;
ESI-MS (m/z): 213 (M+1).
7. (a) Cai, Y.; Wu, Q.; Xiao, Y. M.; Lv, D. S.; Lin, X. F.
J. Biotechnol. 2006, 121, 330–337; (b) Cai, Y.; Wu, Q.;
Wang, N.; Sun, X. F.; Lin, X. F. Chin. Chem. Lett. 2004, 15,
594–596; (c) Cai, Y.; Sun, X. F.; Wang, N.; Lin, X. F.
Synthesis 2004, 5, 671–674; (d) Cai, Y.; Yao, S. P.; Wu, Q.;
Lin, X. F. Biotechnol. Lett. 2004, 26, 525–528.
8. (a) Boon, J. A.; Levinsky, J. A.; Pflug, J. L.; Wilkes, J. S. J. Org.
Chem. 1986, 51, 480–483; (b) Sheldon, R. Chem. Commun.
2001, 2399–2407; (c) Kim, Y. J.; Varma, R. S. Tetrahedron
Lett. 2005, 46, 7447–7449; (d) Ranu, B. C.; Jana, R. J. Org.
Chem. 2005, 70, 8621–8624; (e) Zhu, A. L.; Jiang, T.; Wang,
D.; Han, B. X.; Liu, L.; Huang, J.; Zhang, J. C.; Sun, D. H.
Green Chem. 2005, 7, 514–517.
9. (a) Joseph, T.; Sahoo, S.; Halligudi, S. B. J. Mol. Catal. A:
Chem. 2005, 234, 107–110; (b) Zhu, H. P.; Yang, F.;
Tang, J.; He, M. Y. Green Chem. 2003, 5, 38–39; (c) Driver,
G.; Johnson, K. E. Green Chem. 2003, 5, 163–169; (d)
Kemperman, G. J.; Roeters, T. A.; Hilberink, P. W. Eur.
J. Org. Chem. 2003, 9, 1681–1686.
10. (a) McNulty, J.; Cheekoori, S.; Nair, J. J.; Larichev, V.;
Capretta, A.; Robertson, A. J. Tetrahedron Lett. 2005, 46,
3641–3644; (b) Jorapur, Y. R.; Lee, C. H.; Chi, D. Y. Org.
Lett. 2005, 7, 1231–1234; (c) Horikawa, M.; Busch-Peterson,
J.; Corey, E. J. Tetrahedron Lett. 1999, 40, 3843–3846; (d)
Corey, E. J.; Zhang, F. Y. Org. Lett. 1999, 1, 1287–1290; (e)
Yadav, J. S.; Reddy, B. V. S.; Baishya, G. J. Org. Chem.
2003, 68, 7098–7100; (f) Ranu, B. C.; Dey, S. S. Tetrahedron
2004, 60, 4183–4188; (g) Xu, L. W.; Li, J. W.; Zhou, S. L.;
Xia, C. G. New J. Chem. 2004, 28, 183–184; (h) Zhang,
F. Y.; Corey, E. J. Org. Lett. 2000, 2, 1097–1100.
4.2.19. 3-(6-Benzylamino-purin-1-yl)-propionic acid
methyl ester (5f). Yellow solid, mp 124–125 ꢀC; IR
1
(KBr): 3366, 3097, 1724, 1613 cmꢂ1; H NMR (CDCl3, d,
ppm): 8.52 (s, 1H), 7.87 (s, 1H), 7.41–7.27 (m, 5H), 6.45
(t, 1H), 4.85 (d, 2H), 4.59 (t, 2H, J¼6.0 Hz), 3.63 (s, 3H),
2.92 (t, 2H, J¼6.0 Hz); 13C NMR (CDCl3, d, ppm): 171.6,
155.0, 153.4, 140.7, 138.8, 128.9, 128.0, 127.7, 121.0,
52.3, 42.0, 39.6, 34.2; ESI-MS (m/z): 312 (M+1).
Acknowledgements
This investigation has enjoyed financial support from the
Natural Science Foundation of China (NO. 20572099).
Supplementary data
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2006.11.013.
References and notes
1. (a) Geen, G. R.; Kincey, P. M.; Choudary, B. M. Tetrahedron
Lett. 1992, 33, 4609–4612; (b) Kato, K.; Ohkawa, S.; Terec,
S.; Terashita, Z.; Nishikawa, K. J. Med. Chem. 1985, 28,
287–294; (c) Butters, M.; Ebbs, J.; Green, S. P.; MacRae,
J.; Morland, M. C.; Murtiashaw, C. W.; Pettman, A. J. Org.
Process Res. Dev. 2001, 5, 28–36; (d) Bando, T.; Jida, H.;
Tao, Z. F.; Narita, A.; Fukuda, N.; Yamon, T.; Sugiyama,
H. Chem. Biol. 2003, 10, 751–758; (e) Tanitame, A.;
Oyamada, Y.; Ofuji, K.; Fujimoto, M.; Iwai, N.; Hiyama,
Y.; Suzuki, K.; Ito, H.; Terauchi, H.; Kawasaki, M.; Nagai,
K.; Wachi, M.; Yamagishi, J. J. Med. Chem. 2004, 47,
3693–3696.
2. (a) Perlmutter, K. Conjugate Addition Reactions in Organic
Synthesis; Pergamon: New York, NY, 1992; p 114; (b)
Ambhaikar, N. B.; Snyder, J. P.; Liotta, D. C. J. Am. Chem.
Soc. 2003, 125, 3690–3691; (c) Sani, M.; Bruche, L.; Chiva,
G.; Fustero, S.; Piera, J.; Volonterio, A.; Zanda, M. Angew.
Chem., Int. Ed. 2003, 42, 2060–2063; (d) Fadini, L.; Togni,
A. Chem. Commun. 2003, 30–31; (e) Adrian, J. C.; Snapper,
M. L. J. Org. Chem. 2003, 68, 2143–2150.
11. Abello, S.; Medina, F.; Rodriguez, X.; Cesteros, Y.; Salagre, P.;
Sueiras, J. E.; Tichit, D.; Coq, B. Chem. Commun. 2004, 1096–
1097.
12. Ranu, B. C.; Banerjee, S. Org. Lett. 2005, 7, 3049–3052.
13. Xu, J. M.; Liu, B. K.; Wu, W. B.; Qian, C.; Wu, Q.; Lin, X. F.
J. Org. Chem. 2006, 71, 3991–3993.
14. Xu, J. M.; Wu, W. B.; Qian, C.; Liu, B. K.; Lin, X. F.
Tetrahedron Lett. 2006, 47, 1555–1558.
15. (a) Aggarwal, A.; Lancaster, N. L.; Sethi, A. R.; Welton, T.
Green Chem. 2002, 4, 517–520; (b) Ross, J.; Xiao, J. L.
Chem.—Eur. J. 2003, 9, 4900–4906.
16. (a) Crowhurst, L.; Lancaster, N. L.; Arlandis, J. M. P.; Welton, T.
J. Am. Chem. Soc. 2006, 126, 11549–11555; (b) Meciarova, M.;
Toma, S.; Kotrusz, P. Org. Biomol. Chem. 2006, 4, 1420–1424;
(c) Lancaster, N. L. J. Chem. Res., Synop. 2005, 413–417.