Microwave-assisted liquid-phase synthesis of methyl 6-amino-5-cyano-4-aryl- 2-methyl-4H-pyran-3-carboxylate using functional ionic liquid as soluble support

Article abstract of DOI:10.1016/j.tetlet.2005.03.197

A microwave-assisted liquid-phase synthesis of methyl 6-amino-5-cyano-4- aryl-2-methyl-4H-pyran-3-carboxylate was developed using functional ionic liquid as soluble support. IL-bound acetoacetate was treated with arylidenemalononitriles to give supported 4H-pyran derivatives. After cleavage, the target compounds were obtained in good yields and high purities without chromatographic purification.

Full text of DOI:10.1016/j.tetlet.2005.03.197

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3931–3933
Microwave-assisted liquid-phase synthesis of methyl
6-amino-5-cyano-4-aryl-2-methyl-4H-pyran-3-carboxylate
using functional ionic liquid as soluble support
Fengping Yi, Yanqing Peng and Gonghua Song*
Shanghai Key Laboratory of Chemical Biology, Institute of Pesticides and Pharmaceuticals,
East China University of Science and Technology, Shanghai 200237, China
Received 27 December 2004; revised 3 March 2005; accepted 4 March 2005
Available online 13 April 2005
Abstract—A microwave-assisted liquid-phase synthesis of methyl 6-amino-5-cyano-4-aryl-2-methyl-4H-pyran-3-carboxylate
was developed using functional ionic liquid as soluble support. IL-bound acetoacetate was treated with arylidenemalononitriles to
give supported 4H-pyran derivatives. After cleavage, the target compounds were obtained in good yields and high purities without
chromatographic purification.
Ó 2005 Published by Elsevier Ltd.
Combinatorial chemistry has emerged as a powerful
tool to generate large numbers of compounds for the
screening of functional molecules.1 In the field of
combinatorial chemistry, solid-phase organic synthesis
(SPOS) has been accepted as an efficient method for
high-throughput synthesis.2 Despite its great success,
solid-phase synthesis still exhibits several shortcomings
such as the nature of heterogeneous reaction and diffi-
culties in reaction monitoring. By replacing insoluble
cross-linked resins with soluble polymer supports, the
familiar reaction conditions of classical organic chemis-
try are reinstated, and yet product purification is still
facilitated due to their macromolecular properties.3
Non-crosslinked polystyrene and poly(ethylene glycol)
(PEG) are the most common and useful soluble poly-
mers for liquid-phase organic synthesis.4 However, there
is a main limitation about the use of soluble polymer
supports, namely, low loading capacity. Fluorous
synthesis, which successfully integrates liquid-phase
reaction conditions with the phase-tag separations, has
been recently introduced as a ÔbeadlessÕ high-speed
synthetic technology.5 This is based on the concept that
fluorinated reagents preferentially dissolved in perflu-
oroalkanes, the fluorous phase. But the expense of
perfluoroalkane solvents, limitation in solvent selection,
and the need for specialized reagents may limit its
general applications. So, the idea of searching alterna-
tive soluble supports for high-throughput organic
synthesis has been advocated.
Recently, more attentions in room temperature ionic
liquids research have been paid on the functionalized
ionic liquids with special tasks.6 Functionalized ionic
liquids have been introduced as soluble supports in
liquid-phase organic synthesis.7–10 It has the advantages
of the nature of homogeneous reaction, high loading
capacity, wide range of solvents, simple monitoring
technology, and low cost.
Microwave-assisted reactions have become an estab-
lished tool in organic synthesis.11 Deetlefs and Seddon12
reported that microwave irradiation could accelerate
synthetic reaction for the preparations of ionic liquids.
Hoffmann et al.13 found that ionic liquids could effi-
ciently absorb microwave energy by which the reaction
rate could be accelerated remarkably. Fraga-Dubreuil
et al. reported the synthesis of functionalized ionic liquid
under microwave irradiations9 and one-pot three-
component condensation under microwave dielectric
heating.10
Polyfunctionalized 4H-pyrans constitute a structural
unit of a number of biologically interesting compounds
which possess various pharmacological activities.14 In
this letter, we report our results about the application
of functional ionic liquid as soluble support in the
*
Corresponding author. Tel.: +86 21 642 52945; fax: +86 21 642
51386; e-mail: ghsong@ecust.edu.cn
0040-4039/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.03.197

3932
F. Yi et al. / Tetrahedron Letters 46 (2005) 3931–3933
BF4
Cl
i
+
+
ii
iii
N
N
N
N
N
N
N
N
H3C
H3C
H3C
O
OH
H3C
OH
2
1
3
O
O
Ar
O
BF4
BF4
+
iv
+
N
N
CN
O
CH3
H3C
O
4
H3C
NH2
5a-h
O
Ar
O
CN
v
CH3O
H3C
6a-h
NH2
Scheme 1. Reagents and conditions: (i) chlorohydrin (2 equiv), N2, microwave 200 W, reflux, 2 min; (ii) NaBF4 (2 equiv), CH3CN, 80 °C, 24 h;
(iii) ethyl acetoacetate (3 equiv), microwave 200 W, reflux, 10 min; (iv) arylidenemalononitriles (2 equiv), pyridine, acetonitrile, microwave 200 W,
reflux, 15–20 min; (v) sodium methoxide, methanol, room temperature, 6 h.
Table 1. IL-supported liquid-phase synthesis of 4H-pyrans
liquid-phase synthesis of methyl 6-amino-5-cyano-4-
aryl-2-methyl-4H-pyran-3-carboxylates (Scheme 1).
Entry Ar
Timea Yieldb Final Purityd
(min) (%)
yieldc (%)
(%)
Strohmeier and Kappe15 reported the transesterification
of standard polystyrene Wang resin with ethyl aceto-
acetate both under conventional and microwave condi-
tions in solid phase organic synthesis. In our research,
ionic liquids 1-(2-hydroxyethyl)-3-methylimidazolium
tetrafluoroborate ([2-hydemim][BF4]) 3 was treated with
ethyl acetoacetate under microwave irradiation to offer
intermediate 4. As indicated by IR monitoring, only
10 min was needed for the transformation from 3 to 4.
in contrast, it would take 3 h for the same conversion
under conventional condition. Cyclization between IL-
bound acetoacetate 4 and arylidenemalononitriles gave
bound 4-H pyran derivatives 5a–h. The excess reactant,
arylidenemalononitriles, could be removed by simple
extraction with the mixture of petroleum ether and
dichloromethane (1:1 v/v), due to the immiscibility be-
tween ionic liquid phase and the mixture of petroleum
ether and dichloromethane. Finally, the 5a–h was trea-
ted with sodium methoxide in methanol for 6 h at room
temperature. On completion of the cleavage step (moni-
tored by TLC), the methanol in reaction mixture was re-
moved in vacuo, and the product was extracted from the
residue with dichloromethane. After the removal of
dichloromethane, methyl 6-amino-5-cyano-4-aryl-2-
methyl-4H-pyran-3-carboxylates 6a–h were obtained in
high yields and purities without further purification
(Table 1).
1
2
3
4
5
6
7
8
C6H5
20
20
20
15
20
15
15
95
93
94
97
93
96
96
94
88
84
86
91
86
90
90
85
96
98
98
99
97
99
98
95
4-OH–C6H4
4-OCH3–C6H4
4-Cl–C6H4
4-CH3–C6H4
3-NO2–C6H4
3-Br–C6H4
4-OH–3-OCH3–C6H3 20
a Reaction time of step iv, Scheme 1.
b Yields of 5a–h based on 4.
c Isolated yields of final products 6a–h based on 4.
d Determined by HPLC.
run. The yield of 6a maintained at 87–90% in the first
six cycles.
In conclusion, the use of hydroxyl-functionalized ionic
liquids as soluble supports in liquid-phase synthesis of
the title compounds offers considerable advantages:
firstly, the reaction is performed in homogeneous solu-
tion; secondly, higher loading capacity is achieved due
to lower molecular weight of functionalized ionic liquid;
thirdly, because the intermediates can be purified by
simple extraction, the presented methodology is compat-
ible with automatic manipulation; fourthly, the desired
products can be obtained in high yields and purities
without further chromatographic purification. Finally,
the recovered ionic liquid after cleavage can be reused
in another cycle without losing its activity.
To recover the hydroxyl-functionalized ionic liquid [2-
hydemim][BF4], the residue after extraction was washed
twice with dichloromethane, and then acetone was
added. The precipitate was removed and the filtrate
was concentrated in vacuo to give regenerated [2-hyde-
mim][BF4]. The IL-bound acetoacetate 4 was synthe-
sized in the same way described previously using
recovered [2-hydemim][BF4] and employed in the next
Acknowledgements
Financial support for this work from the National Key
Project for Basic Research (2003 CB 114402, The Min-

F. Yi et al. / Tetrahedron Letters 46 (2005) 3931–3933
3933
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Supplementary data
Supplementary data associated with this article can
be found in the online version, at doi:10.1016/
j.tetlet.2005.03.197.
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