Tetramethylguanidine-[bmim][BF4]. An efficient and recyclable catalytic system for one-pot synthesis of 4H-pyrans

Article abstract of DOI:10.1007/s00706-004-0270-y

A clean and efficient method for the synthesis of 4H-pyran derivatives through the one-pot condensation of aromatic aldehydes, malononitriles, and β-dicarbonyl compounds, using guanidine base tetramethylguanidine in [bmim] [BF₄] ionic liquid as

Full text of DOI:10.1007/s00706-004-0270-y

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Monatshefte f€ur Chemie 136, 727–731 (2005)
DOI 10.1007/s00706-004-0270-y
Tetramethylguanidine-[bmim][BF4].
An Efficient and Recyclable Catalytic
System for One-Pot Synthesis of 4H-Pyrans
Ã
Yanqing Peng, Gonghua Song , and Feifei Huang
Shanghai Key Laboratory of Chemical Biology, Institute of Pesticides & Pharmaceuticals,
East China University of Science and Technology, Shanghai 200237, China
Received July 27, 2004; accepted (revised) October 4, 2004
Published online February 11, 2005 # Springer-Verlag 2005
Summary. A clean and efficient method for the synthesis of 4H-pyran derivatives through the one-pot
condensation of aromatic aldehydes, malononitriles, and ꢀ-dicarbonyl compounds, using guanidine
base tetramethylguanidine in [bmim][BF4] ionic liquid as a recyclable catalytic system, was described.
Keywords. Ionic liquid; Catalysts; Guanidine; Cyclization; One-pot; 4H-Pyrans.
Introduction
In recent years one of the prime concerns of chemists is search for replacements of
the toxic and=or flammable conventional organic solvents with environmentally
benign ones [1]. In this context, room temperature ionic liquids have recently re-
ceived recognition as an eco-friendly alternative to replace volatile organic solvents
that are currently used as solvents in both academic and industrial processing [2].
Polyfunctionalized 4H-pyrans constitute a structural unit of a number of natural
products [3] and because of the inherent reactivity of the pyran ring are versatile
synthons [4]. In addition, polyfunctionalized 4H-pyrans are biologically interesting
compounds which possess various pharmacological activities [5], e.g. antiallergic
[6] and antitumor [7] activities. In the family of polyfunctionalized 4H-pyrans,
apart from the biological activities of themselves, 4H-pyrans are also useful inter-
mediates for the synthesis of various compounds, such as pyranopyridine deriva-
tives [8], polyazanaphthalenes [9], pyrano[2,3-d]pyrazoles [9], pyrano[2]pyrimidines
[10] and pyridin-2-ones [11], with potential biological activities. Moreover,
4H-pyrans can be transformed into corresponding pyridines related to important
DHP type calcium antagonists [12].
Ã
Corresponding author. E-mail: ghsong@ecust.edu.cn

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Y. Peng et al.
Scheme 1
Routinely, 5-substituted-2-amino-4-aryl-3-cyano-6-methyl-4H-pyrans were
prepared through the cyclization of arylidenemalononitriles with 1,3-dicarbonyl
compounds in the presence of an organic base such as piperidine, pyridine, or
triethylamine [8–10, 13]. Recently, Shestopalov and co-workers [14] have
developed a one-pot electrochemical synthesis of title compounds catalyzed by
electrogenerated base. Most of these reactions were carried out in volatile and
flammable organic solvents such as ethanol with the yields ranged from 60 to 80%.
In addition, the recovery of catalysts is also a tedious and energy-consuming
procedure.
In view of the emerging importance of ionic liquids as environmentally friendly
and recyclable reaction media, we report herein an efficient one-pot preparation of
title compounds promoted by a strong guanidine base [15], 1,1,3,3-tetramethylgua-
nidine (TMG), using ionic liquid [bmim][BF4] as the solvent (Scheme 1).
Results and Discussions
Initially, to investigate the influence of different solvents on the cyclization, the
condensation between benzaldehyde, malononitrile, and ethyl acetoacetate was
chosen as a model. In a blank experiment, the equimolar mixture of benzaldehyde
(5 mmol), malononitrile (5 mmol), and ethyl acetoacetate (5 mmol) was heated in
3 cm3 of ethanol at 80ꢀC. After being stirred for 3 hours, it gave no product. Then
10 mol-% of TMG were added and the mixture was heated for 1.5 h at the same
temperature. The desired product was obtained in 81% yield. It was found that
ionic liquids had superiority over ethanol in view of higher isolated yields and
reaction rates. There are no considerable differences in reaction rates and yields
either with TMG-[bmim][BF4] (83%, 50 min) or with the TMG-[bmim][PF6] (84%,
50 min) catalytic system. These data point out an accelerating effect of the ionic
solvents. Possibly, the ionic nature of the imidazolium ionic liquids could facilitate
the reaction by providing stabilization of reactive charged intermediates [16]. It is
worth mentioning that, if the ionic liquid was used in the absence of organic base,
no reaction was observed after 3 h. In our procedure, [bmim][BF4] was chosen due
to its hydrophilicity, by which the final treatment was facilitated.

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Tetramethylguanidine-[bmim][BF4]
729
Table 1. One-pot synthesis of 5-acyl=alkoxycarbonyl-2-amino-4-aryl-3-cyano-6-methyl-4H-pyrans
in [bmim][BF4] catalyzed by TMG
Time
min
Entry
Ar
R
Products
Yield=%a
1
2
C6H5
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
Me
3a
3b
3c
3d
3e
3f
50
30
90
30
30
70
90
40
60
70
90
40
83
87
82
81
85
80
78
89
82
80
81
85
4-Cl–C6H4
4-MeO–C6H4
3-NO2–C6H4
4-CN–C6H4
4-OH–C6H4
3-MeO–4-OH–C6H3
2,4-Cl2–C6H3
C6H5
3
4
5
6
7
3g
3h
3i
8
9
10
11
12
4-MeO–C6H4
4-Me–C6H4
3-NO2–C6H4
Me
3j
Me
3k
3l
Me
a
isolated yields
The scope and generality of this process were next examined with a variety of
other substrates (Table 1). In all the cases tested, the cyclization went smoothly
with 10 mol-% of TMG under similar reaction conditions, giving the correspond-
ing 4H-pyran derivatives in good yields. Condensations were carried out in
[bmim] [BF4] at 80ꢀC for times ranging from 0.5 to 1 h. Yields, usually on the
order of 78–89%, were obtained almost routinely (Table 1). The electronic effects
of phenyl ring substituents were also explored. It is seen from Table 1 that electron-
donating groups disfavor product formation as demonstrated for 3c, 3f, and 3g, and
electron-withdrawing groups favor the formation of product as shown for 3d and
3e, respectively. Additionally, that electron-withdrawing groups favor the forma-
tion of products is further supported with a sterically hindered substrate bearing
electron-withdrawing groups (Table 1, Entry 8, 3h).
As a second idea, we studied the extension of our procedure to the formation of
5-acetyl-2-amino-4-aryl-3-cyano-6-methyl-4H-pyrans using acetylacetone under
similar conditions (Table 1, Entry 9–12). In accord with our expectation, these
reactions proceeded smoothly and afforded corresponding products in good yields.
From the environmental and economic points of view, another advantage of this
procedure is that the catalyst-containing solvent can be easily recovered and reused
in subsequent reactions. Since the 4H-pyran products were weakly soluble in aqu-
eous ionic phase, after reaction, the paste-like mixture thus obtained was diluted
with a certain amount of water, the crude product precipitated was filtered off and
the catalyst and solvent, [bmim][BF4], were recovered easily by removing water
under reduced pressure and drying at 100ꢀC for several hours. The recovered TMG-
IL could be reused in subsequent reactions, affording similar isolated yields of title
compounds.
Investigations by using benzaldehyde, malononitrile, and ethyl acetoacetate as
model substrates showed that successive reuse of the recovered ionic liquids and
the catalyst gave the product with a yield similar to the first round. As shown in

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730
Y. Peng et al.
Fig. 1. Recycling studies of TMG-[bmim][BF4] system
Fig. 1, catalyst-containing ionic liquid can be recycled at least five times with
essentially no loss in catalytic activity. It is noteworthy that the product was iso-
lated in 88% yield (Fig. 1, Run 3) even without any replenishment of the catalyst,
indicating that both the ionic liquid and the catalyst were recyclable and reusable.
In conclusion, we have developed a TMG-catalyzed clean synthesis of bio-
logically interesting 4H-pyrans in good isolated yields using a room temperature
ionic liquid [bmim][BF4] as recyclable medium. In comparison with the pre-
viously reported methods, the following advantages were achieved: (1) without
any additional volatile solvent, (2) simple work-up, and (3) reusable catalyst-
solvent system.
Experimental
All products are known compounds, their physical and spectroscopic data were compared with those
reported in the literature and found to be identical. Melting points were determined on a X-4 micro-
melting point apparatus and are uncorrected. IR spectra were recorded as KBr pellets with a Nicolet
1
Nexus 470 spectrophotometer. H NMR spectra were recorded on a Bruker AM 500 spectrometer in
acetone-d6 with TMS as an internal standard.
General Procedure
To a 25 cm3 round bottomed flask containing aromatic aldehydes (5mmol), malononitrile (5mmol),
and ethyl acetoacetate (or acetylacetone) (5 mmol) was added TMG (0.5mmol) and [bmim][BF4]
(3cm3). The mixture was then heated at 80ꢀC for the indicated time (Table 1). The product separated
out from the homogeneous mixture subsequently as the reaction progressed. After completion of the
reaction (monitored by TLC), 1 cm3 of water was added to the mixture, and the crude product was
collected by filtration, washed with water, air dried, and recrystallized from 95% EtOH to afford pure
products.
The catalyst-containing ionic phase was recovered easily by removing water under reduced pres-
sure and drying at 100ꢀC for 2 h.