Imidazolium-based phosphinite ionic liquid as reusable catalyst and solvent for one-pot synthesis of 3,4-dihydropyrimidin-2(1H)-(thio)ones

Article abstract of DOI:10.1002/hc.20549

A mild and efficient procedure for the synthesis of 3,4-dihydropyrimidin- 2(1H)-(thio)ones in phosphinite ionic liquid is described. This ionic liquid plays a dual role as both the reaction media and also a catalyst, which can be easily recovered and reus

Full text of DOI:10.1002/hc.20549

Heteroatom Chemistry
Volume 20, Number 5, 2009
I
midazolium-Based Phosphinite Ionic Liquid
as Reusable Catalyst and Solvent for One-Pot
Synthesis of 3,4-Dihydropyrimidin-2(1H)-
(
thio)ones
1
2
Hassan Valizadeh and Abbas Shockravi
1
Department of Chemistry, Faculty of Sciences, Azarbaijan University of Tarbiat Moallem,
Tabriz, Iran
2
Faculty of Chemistry, University of Tarbiat Moallem, Tehran, Iran
Received 31 March 2009; revised 28 May 2009
chemistry have also been reported, for instance in
ABSTRACT: A mild and efficient procedure for the
alkylations [4], benzoin condensation [5], and Diels–
Alder [6], and Friedel–Crafts [7] type reactions. Fur-
thermore, their possible use for selective extraction
of organic compounds has been noted recently [8].
synthesis of 3,4-dihydropyrimidin-2(1H)-(thio)ones
in phosphinite ionic liquid is described. This ionic
liquid plays a dual role as both the reaction media
and also a catalyst, which can be easily recovered
and reused in several runs. ꢀC 2009 Wiley Periodicals,
Dihydropyrimidinones (DHPMs) have attracted
considerable attention because of their wide
Inc. Heteroatom Chem 20:284–288, 2009; Published on-
spectrum of biological and therapeutic activities.
line in Wiley InterScience (www.interscience.wiley.com).
Functionalized DHPMs have been used as potent
DOI 10.1002/hc.20549
calcium channel blockers [9], antihypertensive
agents [10], and neuropeptide Y antagonists [11].
The Biginelli reaction is a well-known, simple,
INTRODUCTION
and straightforward procedure for the synthesis of
DHPMs by the three-component condensation of
aliphatic or aromatic aldehyde, acetoacetate ester,
and urea [12]. There is a variety of suitable reaction
conditions, traditionally with strong Bronsted acid,
but nowadays, more frequently, with Lewis acids
Ionic liquids are a new class of solvents, which have
attracted growing interest over the past few years
due to their unique physical and chemical proper-
ties [1]. They usually consist of poorly coordinating
ion pairs, and a classical example is the readily ac-
cessible 1-butyl-3-methylimidazolium tetrafluorob-
orate [bmim][BF4], which is a colorless mobile but
nonvolatile liquid with no smell [2]. Since such sol-
vents easily dissolve metal salts and transition metal
catalysts, interesting developments have recently ap-
peared in synthesis using organometallic reagents
[13] for the synthesis of DHPMs via the Biginelli
reaction. Many novel and useful adaptations of the
Biginelli reaction have been described in the liter-
ature, including those employing microwaves [14],
solid-phase synthesis [15], ionic liquids [16], silica
gel supported sodium hydrogensulfate [17], and
polymer-supported catalysts [18]. In recent years,
there has been an increasing interest in reactions
that proceed in task-specific ionic liquids (TSILs)
as a powerful alternative to conventional molecular
organic solvents or catalysts due to their particular
properties, such as undetectable vapor pressure,
wide liquid range, as well as the ease of recovery
[3]; some applications of these solvents in organic
Correspondence to: Hassan Valizadeh; e-mail: h-valizadeh@
azaruniv.edu.
Contract grant sponsor: Research Vice Chancellor of Azarbaijan
University of Tarbiat Moallem, Tabriz, Iran.
ꢀ
c 2009 Wiley Periodicals, Inc.
284

Imidazolium-Based Phosphinite Ionic Liquid as Reusable Catalyst and Solvent 285
Ar
H
O
X
O
O
EtO C
2
IL-OPPh2
NH
+
+
o
Ar
H
H N
NH2 Me
OEt
2
100 C
Me
N
X
H
1
2
3
4
4
a: Ar=Ph, X=O
4
j: Ar=2-Thienyl, X=O
4
4
b: Ar=4-Me-Ph, X=O
c: Ar=4-NO -Ph, X=O
4k: Ar=2-Furyl, X=O
4l: Ar=Ph, X=S
4m: Ar=4-Me-Ph, X=S
2
2
2
a: X=O
b: X=S
4d: Ar=2-NO -Ph, X=O
4e: Ar=4-Cl-Ph, X=O
2
4n: Ar=4-MeO-Ph, X=S
4
4
4
4
f: Ar=3-Cl--Ph, X=O
g: Ar=2-Cl--Ph, X=O
h: Ar=2-Me-Ph, X=O
i: Ar=2-Pyridyl, X=O
4o: Ar=4-Cl-Ph, X=S
4p: Ar=2-Thienyl, X=S
4q: Ar=3-NO -Ph, X=S
2
SCHEME 1
and reuse [19]. Zuliang et al. used room temper-
ature TSILs, 3-trialkylammoniopropanesulfonate,
for the synthesis of DHPMs [19c]. Shaabani and
Rahmati [20] used room temperature ionic liquid
Synthesis of 3,4-Dihydropyrimidin-2(1H)-(thio)-
ones (4a–q): General Procedure
A
mixture of arylaldehyde (5 mmol), 1,3-
dicarbonyl compound (6.25 mmol), urea or thiourea
1
,1,3,3-tetramethylguanidinium
as catalyst, Li et al. [21] reported ionic liquid
BMImSac) as catalyst, Zheng et al. [22] synthesized
and used ionic liquid CMImHSO as catalyst for the
trifluoroacetate
(
1
5.75 mmol), and IL-OPPh
00 C under stirring. The reaction was monitored by
2
(5 mmol) was heated at
◦
(
TLC using ethyl acetate/hexane (2:5) as eluent. After
cooling to room temperature, the reaction mixtures
were extracted with ether and ethylacetate (8 mL ×
4
Biginelli reaction. Our recent interest is in the area
of green synthesis under conventional heating as
well as microwave conditions [23]. In this paper, a
task-specific ionic liquid (phosphonite ionic liquid,
3). The organic layers were collected and concen-
trated in vacuum. The residual solid was recrystal-
lized from ethyl acetate or ethanol to afford pure
product.
IL-OPPh ), with weak Lewis basic character, was
2
synthesized and used as catalyst for the one-pot syn-
thesis of 3,4-dihydropyrimidinones or their sulfur
analogues via the Biginelli reaction (Scheme 1).
Recyclability of IL-OPPh2
After carrying out the reaction, the mixture was ex-
tracted with the mixture of ether and ethyl acetate
(
8 mL × 3) to remove all adsorbed organic sub-
EXPERIMENTAL
strates. Then the remained ionic liquid (IL) was dried
in a vacuum oven and reused in the next cycle di-
rectly without further purification.
General Information
Task-specific ionic liquid was prepared according to
the procedure reported in the literature [24,25]. All
chemicals were purchased from Merck and used as
RESULTS AND DISCUSSION
1
received. H NMR spectra (400 MHz) were recorded
on a Bruker Avance spectrometer using TMS as
internal standard. Infrared spectra were recorded in
KBr and were determined on a Perkin Elmer FT-IR
spectrometer. Elemental analyses were carried out
on a Perkin–Elmer 240C elemental analyzer and
are reported in percent atomic abundance. All
melting points are uncorrected and measured in
an open glass-capillaries using Stuart melting point
apparatus.
We have recently introduced an imidazolium-based
phosphinite ionic liquid for the Horner–Wadsworth–
Emmons type reaction [26]. In this report, the ionic
liquid plays a dual role both as a reagent via its
phosphinite-carrying group and also as the reac-
tion media. Here, we report a new application of
this ionic liquid as solvent and catalyst for the
mild and efficient synthesis of Biginelli products in
the absence of any acid catalyst (Scheme 1). The
Heteroatom Chemistry DOI 10.1002/hc

286 Valizadeh and Shockravi
◦
TABLE 1 Synthesis of Dihydropyrimidin-2(H)-ones and Thiones in IL-OPPh at 100 C
2
◦
Mp (C)
Reported [Ref.]
Producta
Time (h)b
Found
Yield (%)
c
Entry
X
Ar
1
2
3
4
5
6
7
8
9
O
O
O
O
O
O
O
O
O
O
O
S
Ph
4-Me-Ph
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
2.5
3
1.5
3
1.3
1.5
3
1.4
2.5
2
1.5
2
2.1
3.5
3
2.5
2
205–207
204–206
210–212
220–221
212–213
192–194
228–229
202–204
193–195
214–216
206–208
204–206
192–195
148–149
179–182
193–195
206–208
206–208 [27]
205–206 [27]
211–213 [28]
221 [29]
91
89
95
90
89
91
92
93
94
88
89
90
91
92
93
94
90
4-NO -Ph
2
2-NO -Ph
2
4-Cl-Ph
3-Cl-Ph
212–213 [30]
193–195 [31]
229–231 [13e]
202–204 [32]
194–195 [30]
215–217 [32]
206–208 [22]
205–206 [33]
192–194 [32]
150–152 [32]
180–182 [33]
193–194 [34]
206–207 [27]
3-NO -Ph
2
4-MeO-Ph
2-Pyridyl
2-Thienyl
2-Furyl
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
Ph
S
S
S
S
4-Me-Ph
4-MeO-Ph
4-Cl-Ph
4-OH-Ph
S
3-NO -Ph
2
a
1
Products were characterized by comparison of their spectroscopic data ( H NMR and IR) and melting points with those reported in the
literature.
Determined by TLC.
b
c
Yields of recrystallized products.
reaction between benzaldehyde, urea 2a, and ethy-
lacetoacetate in IL-OPPh leads to the formation of
3,4-dihydropyrimidinones were recorded in these
conditions.
2
related dihydropyrimidine 4a. The reaction mixture
was stirred at 100 C in a preheated oil bath. Next, to
A plausible mechanism for the formation of the
◦
selected product 4a in the presence of IL-OPPh
2
improve the yields, we performed the reactions using
different quantities of reagents. The best results were
obtained with a 1:1.15:1.25:1 ratio of aldehyde, urea,
as a weak base catalyst is outlined in Scheme 2.
Intermediate 5 apparently results from the initial
Knoevenagel condensation of ethylacetoacetate with
ß-ketoester, and IL-OPPh
2
, respectively. Several
benzaldehyde in the presence of IL-OPPh as a Lewis
2
DHPMs were successfully synthesized in high yields
by following the above method. The products can be
separated from the ionic liquid system by simple ex-
traction with ether and ethyl acetate in all examined
cases. The results of the transformation of differently
substituted aryl aldehydes to DHPM derivatives 4a–q
are presented in Table 1. Aromatic aldehydes bearing
both electron-donating and electron-withdrawing
groups readily undergo the reaction, giving fair
yields of the corresponding Biginelli compounds. All
products are known compounds, characterized by
base catalyst. Michael addition of urea to the 5 yields
the intermediate 6, which cyclizes to cyclic imine
7 via the intramolecular condensation reaction.
Compound 7 is converted to stable enamine product.
A noteworthy feature of ILs is their recyclability.
In the present study, we investigated that IL-OPPh
2
can be recycled. After removal of the mixture of prod-
uct, possible impurities and unreacted materials, the
remaining IL was reused for consecutive three cycles
without loss in their efficiency (Table 2).
1
TABLE 2 The Comparison of Efficiency of IL-OPPh2 in Syn-
thesis of Biginelli Products 4a and 4l after Three Times
mp, IR, H NMR spectra, and elemental analysis.
To exhibit the catalytic effect of IL-OPPh ,
2
Yield(%)a
the condensation of two arylaldehydes (4-
nitrobenzaldehyde and 4-methoxybenzaldehyde)
with ethylacetoacetate and urea was studied by
using different imidazolium-based ILs includ-
Run
4a
4l
1
2
3
91
90
91
90
90
89
ing [bmim] Cl, [bmim] Br, and [bmim] BF
4
at
◦
100 C. It was found that these ILs were no more
aYields of recrystallised product.
effective, and poor yield of the corresponding
Heteroatom Chemistry DOI 10.1002/hc

Imidazolium-Based Phosphinite Ionic Liquid as Reusable Catalyst and Solvent 287
O
H
H
PF6
CO2Et
..
N
+
N
OPPh2
EtO C
COMe
2
2O
O
Me
5
.
.
NH
2
O
NH2
H
CO Et
2
CO Et
HN
2
HN
2O
O
O
N
Me
..
O
NH
Me
2
7
6
CO Et
2
HN
O
N
Me
H
4a
SCHEME 2
CONCLUSION
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Heteroatom Chemistry DOI 10.1002/hc