Microwave accelerated facile and efficient synthesis of piperido[3′,4′:5,6]pyrano[2,3-d] pyrimidinones catalyzed by basic ionic liquid [BMIM]OH

Article abstract of DOI:10.1016/j.molcata.2013.10.026

A basic ionic liquid [BMIM]OH could very efficiently catalyze the synthesis of piperido[3′,4′:5,6]pyrano[2,3-d]pyrimidinone derivatives from pyrano[3,2-c]piperidine analogues and carbonyl compounds. [BMIM]OH acted as a catalyst as well as the reaction medium and could be used for the reactions for five times without any appreciable loss of its catalytic efficiency. The synergic couple of microwave and ionic liquid provided high yields of the product in very short reaction times and allowed easy workup.

Full text of DOI:10.1016/j.molcata.2013.10.026

Journal of Molecular Catalysis A: Chemical 382 (2014) 126–135
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Journal of Molecular Catalysis A: Chemical
journal homepage: www.elsevier.com/locate/molcata
Microwave accelerated facile and efficient synthesis of
piperido[3ꢀ,4ꢀ:5,6]pyrano[2,3-d] pyrimidinones catalyzed by basic
ionic liquid [BMIM]OH
I.R. Siddiqui∗, Arjita Srivastava, Shayna Shamim, Anjali Srivastava, Malik A. Waseem,
Shireen, Rahila, Afaf A.H. Abumhdi, Anushree Srivastava, Pragati Rai
Laboratory of Green Synthesis, Department of Chemistry, University of Allahabad, Allahabad 211002, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 March 2013
Received in revised form 15 October 2013
Accepted 20 October 2013
Available online 9 November 2013
A
basic ionic liquid [BMIM]OH could very efficiently catalyze the synthesis of
piperido[3ꢀ,4ꢀ:5,6]pyrano[2,3-d]pyrimidinone derivatives from pyrano[3,2-c]piperidine analogues
and carbonyl compounds. [BMIM]OH acted as a catalyst as well as the reaction medium and could be
used for the reactions for five times without any appreciable loss of its catalytic efficiency. The synergic
couple of microwave and ionic liquid provided high yields of the product in very short reaction times
and allowed easy workup.
Keywords:
© 2013 Elsevier B.V. All rights reserved.
Basic ionic liquid
Microwave
Pyrimidinone
Catalyst
Synthesis
1. Introduction
are known to have hazardous effect on the environment [9]. The
reaction reported by Pandey et al. [9b] uses l-proline for the syn-
Fused pyrimidinones, specially tricyclic condensed pyrimidi-
none derivatives represent structural architectures of remarkable
physiological efficiency and are found in a number of natu-
ral products and clinical drugs [1]. Pyrano[2,3-d]pyrimidinones
and their fused variants, in particular, exhibit a wide range of
diverse biological properties such as antitumor [2], antibacterial [3],
antihypertensive [4], hepatoprotective [4], cardiotonic [4], antihis-
taminic [5], vasodilatory [6], bronchodilatory [6] and antiallergic
[7] activities. Most of these pharmacological activities are due to
the presence of the annulated uracil species. Nevertheless, the
pharmacological properties of polycyclic derivatives of pyrimidi-
nones have been less well explored so far. Although few protocols
have been reported for the synthesis of pyrano[2,3-d]pyrimidinone
derivatives, most of them make use of conventional and hazardous
catalysts and bases [8] such as p-TsCl, ZnCl2, YbCl3, and bases like
Ca(OH)2, NaOH and Et3N. Most of these catalysts and bases are
accompanied with drawbacks like highly toxic and corrosive prop-
erties, environmentally hazardous nature, etc. and they also do not
provide for recyclability and reuse. Further, most of the reported
methods use organic solvents such as DCM, DMF, CH3CN, etc. which
thesis of pyrimidinone derivatives but a very long reaction time is
required.
As part of eco-compatible organic transformations, ionic liquids
(IL) have received substantial interest from the synthetic com-
munity [10,11] owing to their properties like negligible vapour
pressure, lack of flammability, wide solvation ability, high stabil-
ity, ability to synergistically interact with microwave irradiation,
etc. [12,13]. Today, ionic liquids offer their potential in controlling
a reaction as a catalyst as well as playing a role in rate enhancement
of a reaction [14]. The association of reactant molecules in solvent
cavities due to the internal pressure created by ionic environment
of the ionic liquid is probably responsible for the rate enhance-
ment. Basic ionic liquids have attracted huge interest for a long
time by virtue of their catalytic efficiency and their easy recov-
ery and reuse as compared to the combination of a base and IL
for a base-catalysed process [15]. A basic ionic liquid [BMIM]OH
(1-butyl-3-methylimidazolium hydroxide) has been successfully
employed as a catalyst for Michael addition [16], Knoevenagel
condensation [17], Markovnikov addition, and a number of other
reactions [18]. It has very successfully replaced conventional bases
as it is flexible, non-volatile and non-corrosive. In continuation
of our program to develop simple, efficient, atom economical
and eco-compatible protocols for the synthesis of novel poten-
tially bioactive heterocycles [19], we report herein an efficient,
∗
Corresponding author.
E-mail address: dr.irsiddiqui@gmail.com (I.R. Siddiqui).
1381-1169/$ – see front matter © 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molcata.2013.10.026

I.R. Siddiqui et al. / Journal of Molecular Catalysis A: Chemical 382 (2014) 126–135
127
122.1, 123.6, 136.8; HRMS calcd for C8H16N2O (M+−OH) 139.2182,
O
R1
R1
H
N
found 139.2355.
R2
R3
O
R2
O
NH2
CN
R3
(6)
N
NH
N
2.4. Preparation of solid supported ionic liquid
H3C
[BMIM] OH
H3C
R1
O
MW(10-18 min)
R1
The basic ionic liquid [BMIM]OH was also used on polystyrene
resin as a solid support in order to examine its efficiency. This solid
supported ionic liquid was synthesized according to a reported
procedure [20].
5
7 and 8
Scheme 1. Synthesis of novel piperido[3ꢀ;4ꢀ:5,6]pyrano[2,3-d]pyrimidinone.
facile, microwave-assisted and [BMIM]OH catalyzed synthesis
of novel substituted piperido[3ꢀ,4ꢀ:5,6]pyrano[2,3-d]pyrimidinone
derivatives from pyrano[3,2-c]piperidine analogues (Scheme 1).
[BMIM]OH plays the dual role of a solvent as well as a catalyst in
the reaction.
The starting material pyrano[3,2-c]piperidine analogues (5)
have been obtained by the reaction of N-methyl piperidone (1),
aromatic aldehyde (2) and malononitrile (4) using the basic ionic
liquid [BMIM]OH (Scheme 2).
2.5. Preparation of other basic ionic liquids
The basic ionic liquids 1-butyl-2,3-dimethylimidazolium
hydroxide [BMMIM]OH has been synthesized from [BMMIM]Br
using the same procedure as used for [BMIM]OH. [BMMIM]Br has
in turn, been synthesized following a reported procedure [21]. The
other basic ionic liquids, [BMIM]Im (1-butyl-3-methylimidazolium
imdazolide), [DBU]Ac (1,8-diazabicyclo[5.4.0] undec-7-enium
acetate), [C8DABCO]NTf2 (1-octyl-1,4-diaza[2.2.2]bicyclooctan-
iumbis(trifluoromethylsulfonyl)imide, and 2-[2-(dimethylamino)
ethoxy]ethyl-N,N-diisopropylammonium bis(trifluoromethane-
sulfonyl)imide (Fig. 1) have been synthesized according to reported
procedures [22–24].
2. Experimental
2.1. Materials and Instruments
The starting material N-methyl piperidone (1), aromatic alde-
hydes (2a-f and 6k-o), ketones (6a-j), malononitrile (4), ionic
liquids [BMIM]Br and [BMIM]Cl are commercially available. The
monomode microwave reactor “Monowave 300” (manufactured
by Anton-paar Pvt. Ltd.) was used in all reactions. The instrument
uses a maximum of 850 W magnetron output power (2.45 GHz). The
temperature was recorded using IR temperature sensor. The irra-
diation experiments were performed in temperature control mode
(“as-fast-as-possible”, ramp mode). The reaction times reported are
the ‘hold times’. Care was taken to ensure efficient stirring in all
experiments. All the pH values were measured on Eutech’s Cyber-
Scan pH 510 meter. Melting points were determined by open glass
capillary method (uncorrected). 1H and 13C NMR spectra of the syn-
thesized compounds 5a-f, 7a-o and 8a-e were recorded on a Bruker
Avance II (400 MHz) FT spectrometer at 400 and 100 MHz, respec-
tively, with CDCl3 as solvent. Chemical shifts are reported in parts
per million relative to TMS as internal reference. Mass (EI) spec-
tra were recorded on JEOL D-300 mass spectrometer. Elemental
analysis was performed on an Elementar vario EL.
2.6. General procedure for the synthesis of
2-amino-3-cyano-5,6,7,8-tetrahydro-4H-pyrano[3.2-c]
piperidine 5a
A mixture of 1-methyl-4-piperidone 1 (0.01 mol) and the appro-
priate aldehyde 2a (0.02 mol) in basic ionic liquid [BMIM]OH was
stirred at room temperature for 10 min. The separated solid was fil-
tered and recrystallized from the suitable solvents. The separated
solid (0.01 mol) and malononitrile (0.01 mol) in [BMIM]OH was
stirred at room temperature for 1.5 h. The precipitated product was
filtered off and recrystallized to yield 2-amino-3-cyano-5,6,7,8-
tetrahydro-4H-pyrano[3.2-c]piperidine 5a in good to excellent
yields.
2.6.1. 5a:
(E)-2-amino-3-cyano-4-(4-chlorophenyl)-6-methyl-8-(4-
chlorobenzylidene)-5,6,7,8-tetrahydro-4H-pyrano[3,2-c]pyridine
Yield80%;m.p. = 216–219 ◦C;1HNMR (400 MHz, CDCl3):ı = 2.27
(s, 3H), 3.06 (s, 4H), 3.94 (s, 1H), 6.42 (s, 1H, NH), 6.57 (s, 1H),
7.00–7.15 (m, 4H), 7.22–7.24 (m, 4H). 13C NMR (100 MHz, CDCl3):
ı = 40.9, 44.2, 52.2, 52.4, 58.1, 106.5, 117.3, 124.3, 127.8, 128.8,
130.5, 131.3, 133.3, 133.5, 136.9, 140.3, 146.6, 159.3. Anal. Found:
C, 65.13; H, 4.49; N, 9.92 C23H19Cl2N3O requires C, 65.10; H, 4.52;
N, 9.90.
2.2. Preparation of catalytic basic ionic liquid [BMIM]OH
The basic ionic liquid [BMIM]OH was synthesized according to
a reported procedure [16].
2.3. Characterisation of [BMIM]OH
2.7. General procedure for the preparation of
piperido[3ꢀ,4ꢀ:5,6]pyrano[2,3-d]pyrimidinone 7b catalyzed by
basic ionic liquid [BMIM]OH
IR (neat) 3435, 3060, 1569, 1168 cm−1 1H NMR (400 MHz,
;
CDCl3) ı = 0.81 (t, 3H), 1.17–1.35 (m, 2H), 1.73–1.85 (m, 2H),
3.20–3.27 (bs, 1H), 4.02 (s, 3H), 4.24 (t, 2H), 7.46 (d, 1H), 7.59 (d,
1H), 10.17 (s, 1H); 13C NMR (100 MHz) ı = 13.3, 19.0, 31.6, 36.4, 49.3,
A solution of corresponding 2-amino-3-cyano-5,6,7,8-tetra-
hydro-4H-pyrano[3.2-c]piperidine 5a (1.0 mmol); cyclohexanone
CN
CN
R1
O
O
H2C
(4)
R 1-CHO
O
NH2
CN
R1
R1
(2)
N
[BMIM]OH
rt (1.5 h)
[BMIM]OH
rt (10) min
N
CH3
3
H3C
N
CH3
1
R1
5
Scheme 2. Synthesis of the starting material pyrano[3,2-c]piperidine derivative.

128
I.R. Siddiqui et al. / Journal of Molecular Catalysis A: Chemical 382 (2014) 126–135
N
N
N
N
N
N
N
N
OH
OH
[BMMIM]OH
[BMIM]OH
[BMIM]Im
H
N
N
N
CH3COO
N(SO2CF3)2
N
[C8DABCO]NTf2
[DBU]Ac
O
N
N
N(SO2CF3)2
2-[2-(dimethylamino)ethoxy]ethyl-N,N-diisopropylammonium
bis(trifluoromethanesulfonyl)imide
Fig. 1. Basic Ionic Liquids synthesized.
6b (1.3 mmol) and [BMIM]OH (2 mL) was added in a 10 mL reaction
vial, sealed and irradiated at 90 ◦C for 10 min (hold time). After com-
pletion of the reaction as monitored by TLC, the mixture was cooled
and the resulting precipitate was filtered, washed with brine, and
purified by column chromatography (7:3 EtOAc:hexane) to yield
pure target product 7b.
2.7.1. 7b: 8ꢀ-(4-chlorobenzylidene)-1ꢀ-methyl-5ꢀ-(4-
chlorophenyl)spiro[cyclohexane-1,2ꢀ-piperido
[3ꢀ,4ꢀ:5,6]pyrano[2,3-d]pyrimidine]-4ꢀ(1ꢀH)-one
Reddish brown powder. Yield 93%; m.p. = 305–307 ◦C; 1H NMR
(400 MHz, CDCl3): ı = 1.12–1.23 (m, 2H), 1.37–1.49 (m, 4H),
1.60–1.77 (m, 4H), 2.29 (s, 3H), 3.03 (s, 4H), 3.97 (s, 1H), 6.46 (s,
1H, NH), 6.58 (s, 1H), 7.03–7.18 (m, 4H), 7.23–7.25 (m, 4H), 8.13 (s,
1H, NH). 13C NMR (100 MHz, CDCl3): ı = 19.2, 28.0, 29.7, 36.3, 44.0,
49.7, 52.4, 52.5, 82.0, 106.5, 124.3, 127.6, 128.7, 130.5, 131.5, 133.4,
133.7, 136.9, 140.4, 146.6, 166.7, 168.3. Anal. Found: C, 66.62; H,
5.55; N, 8.01 C29H29Cl2N3O2 requires C, 66.67; H, 5.55; N, 8.03.
Fig. 2. aIsolated yields of the product.
8-tetrahydro-4H-pyrano[3.2-c]piperidine 5a (5.0 mmol); cyclo-
hexanone 6b (6.5 mmol) were charged into a 30 mL reaction vial,
sealed and irradiated at 90 ◦C for 10 min (hold time). After comple-
tion of the reaction as monitored by TLC, the mixture was cooled
and the resulting precipitate was filtered, washed with brine, and
purified by column chromatography (7:3 EtOAc:hexane) to yield
pure target product 7b.
2.8. Recycling of [BMIM]OH
The filtrate containing ionic liquid was extracted with 1:1
EtOAc–Et2O solution using a seperatory funnel, dried in vacuum
at 90 ◦C for 2 h to eliminate any water trapped from moisture to
obtain the pure ionic liquid (confirmed from spectroscopy data)
and reused for subsequent reactions (Fig. 2). This could be used for
the reactions for up to five times without any appreciable loss of
its catalytic efficiency. After five runs, about 50% freshly prepared
ionic liquid was added and the mixture proved very efficient for
many more reactions.
3. Results and discussion
N-Methyl piperidone (1), 4-chlorobenzaldehyde 2a and mal-
ononitrile (4) were chosen as model substrates for the synthesis
of the starting material 5a. The formation of 5a was achieved at
room temperature by a two step reaction sequence catalyzed by
[BMIM]OH. The reaction between model substrates pyrano[3,2-
c]piperidine derivative 5a and cyclohexanone 6b was then carried
out smoothly and provided the best yields (93%) under microwave
irradiation in the presence of basic ionic liquid [BMIM]OH as the
solvent-basic catalyst system.
2.9. General procedure for the preparation of
piperido[3ꢀ,4ꢀ:5,6]pyrano[2,3-d]pyrimidinone 7b catalyzed by
solid supported basic ionic liquid
For
ionic
a
typical reaction process, the solid supported basic
liquid (75 mg-optimized), 2-amino-3-cyano-5,6,7,

I.R. Siddiqui et al. / Journal of Molecular Catalysis A: Chemical 382 (2014) 126–135
129
3.1. Solvent, base and temperature screening for the synthesis of
compound 7b
time was shortened to 5 min, only 72% yield was obtained (Table 1,
entry 7). The increase in reaction time, however, did not affect the
yield of the product (Table 1, entry 8).
In order to explore the effects of other ionic liquids on this
microwave accelerated reaction, different combinations of ionic
liquids such as 1-butyl-3-methylimidazolium chloride ([BMIM]Cl),
1-butyl-3-methylimidazolium bromide ([BMIM]Br), and a base
was used. Surprisingly, both the combinations resulted in very low
yields of the product. The results have been summarized in Table 1.
The combination of [BMIM]Br with DBU (1,8-diazabicyclo[5.4.0]
undec-7-ene) gave only 40% yield in 20 min of irradiation time,
(Table 1, entry 4) and that of [BMIM]Cl gave 44% yield (Table 1,
entry 5). As a comparison, the reaction was also carried out in
the common molecular solvents such as MeOH and DMF which
provided 24% and 37% yields respectively (Table 1, entries 1 and
2) whereas the reaction could not proceed in the presence of
CH3CN (Table 1, entry 3). Several other basic ionic liquids known
to act as a basic catalyst such as [BMIM]Im [22], [DBU]Ac [23],
[C8DABCO]NTf2 [24], 2-[2-(dimethylamino)ethoxy]ethyl-N,N-
diisopropylammonium bis(trifluoromethanesulfonyl)imide [24]
and [BMMIM]OH [25] were also synthesized and their effects
on the reaction were studied. [BMMIM]OH although gave better
yields (80%) (Table 1, entry 9) but the best yields were obtained
by [BMIM]OH (93%) (Table 1, entry 6). [BMIM]Im, [DBU]Ac and
2-[2-(dimethylamino)ethoxy]ethyl-N,N-diisopropylammonium
bis(trifluoromethanesulfonyl)imide gave 54%, 41% and 15% yields
respectively (Table 1, entry 10, 11 and 13). No product formation
was observed in case of [C8DABCO]NTf2 (Table 1, entry 12). The
results clearly indicate that [BMIM]OH was the most effective
solvent-catalyst system for the transformation and it effectively
avoided the use of any other base or solvent in the reaction. This
basic ionic liquid provided excellent yields of the product under
only 10 min of microwave irradiation (Table 1, entry 6) and caused
an increase in the reaction rate as well. The irradiation time was
found to have a significant impact on the yield. When the reaction
3.2. Probable reaction mechanism
The increase in the reaction rate and yields in the presence
of [BMIM]OH and the fact that it remained intact (1HNMR) and
was recycled and reused easily, clearly indicate that [BMIM]OH
played a major part in the reaction as a catalyst as well as the
reaction medium. Studies have shown that ionic liquids owing to
their ionic nature are capable of many types of interactions with
the solute species and transition states, which effectively reduces
the activation energies, thus catalyzing the reaction [26]. In the
case of [BMIM]OH, it has also been reported that the C2-H of the
imidazolium group is capable of forming hydrogen bond and thus
influences the reaction [27] and the hydroxy group of [BMIM]OH
is well known to assist the formation of nucleophilic anions [28].
Buoyed from the above facts, a reaction mechanism has been pos-
tulated in which it has been assumed that the hydroxyl group of
the basic ionic liquid activates the intermediate I by abstracting
its proton and thus making it a better nucleophile in the reaction
and the proton of the imidazolium group (C2-H) forms hydrogen
bonding with the nitrogen of the nitrile group and thus increases
its electrophilicity for the intramolecular nucleophilic attack. For
further insight into its catalytic activity, we designed another ionic
liquid [BMMIM]OH, and as expected, it provided only 80% yield
of the product in 15 min of irradiation time (Table 1, entry 9).
There remains a possibility of weaker hydrogen bonds involving
any other hydrogen of [BMMIM]OH. This proves that the C2-H of
[BMIM]OH plays a significant role in the reaction. The possible role
of [BMIM]OH is shown in the proposed mechanism (Scheme 3).
The amino group of the pyrano[3,2-c]piperidine derivative
reacts with the carbonyl of cyclohexanone to give key interme-
diate I. [BMIM]OH catalyzes the intramolecular Pinner reaction by
Table 1
Solvent, base and temperature screening for the synthesis of compound 7b under microwave irradiation.a
O
Cl
Cl
H
N
O
O
NH2
CN
(6a)
N
NH
N
H3C
Solvent/Base
MW
H3C
O
Cl
Cl
5a
7b
Entry
Solvent
Base
Amount of base (equiv.)
Time (min)
Yieldb (%)
1
2
3
4
5
6
7
8
MeOH
CH3CN
DMF
DBU
DBU
DBU
DBU
DBU
–
–
–
–
–
1.5
1.5
1.5
1.5
1.5
–
–
–
–
–
25
25
25
20
25
10
5
15
15
17
23
25
21
24
-
37
40
44
93
72
93
80
54
41
–
[BMIM]Br
[BMIM]Cl
[BMIM]OH
[BMIM]OH
[BMIM]OH
[BMMIM]OH
[BMIM]Im
[DBU]Ac
9
10
11
12
13
–
–
–
–
–
–
[C8DABCO]NTf2
2-[2(dimethylamino)ethoxy]ethyl-N,N-
diisopropylammonium
15
bis(trifluoromethanesulfonyl)imide
aReaction conditions: pyrano[3,2-c]piperidine derivative 5a (1.0 mmol), cyclohexanone 6b (1.3 mmol), solvent (2 mL).
b
Isolated yields after filtration and purification.

130
Cl
I.R. Siddiqui et al. / Journal of Molecular Catalysis A: Chemical 382 (2014) 126–135
Table 3
C4H9
H3C
Cl
N
N
Comparison of solid supported ionic liquid with non-supported ionic liquids.
O
OH
H
N
O
NH2
CN
Entry
Ionic liquid
Product yield (%)
O
6b
N
O
H
1
2
3
4
5
6
Polystyrene bound [BMIM]OH
[BMIM]OH
[BMIM]Im
[DBU]Ac
[C8DABCO]NTf2
2-[2-(Dimethylamino)ethoxy]ethyl-
N,N-diisopropylammonium
bis(trifluoromethanesulfonyl)imide
80
93
54
41
–
H3C
N
H3C
N
Cl
Cl
I
5a
H2O
15
Cl
Cl
H
N
H
O
O
N
O
N
N
O
3.4. Synthesis of compound 7b in the presence of solid supported
basic ionic liquid and its comparison with the reaction in
non-supported basic ionic liquid
N
H3C
H3C
N
N
H
O
H
H
Cl
Cl
The model reaction was also carried out under microwave irra-
diation in the presence of polystyrene resin supported basic ionic
liquid [BMIM]OH. The results obtained were not very satisfactory
with a substantial decrease in the yield of the product in the same
reaction time (80%). This might be due to the less stability of the
solid support under the reaction conditions. Further, side products
were also observed. A table showing its comparison with non-
supported basic ionic liquids has been presented (Table 3). The
results of Table 3 clearly indicate that the best yields are obtained
with [BMIM]OH (Table 3, entry 2). The solid supported ionic liquid
although provides good yields (Table 3, entry 1), but the best yields
are obtained by using [BMIM]OH as solvent as well as a catalyst.
H3C
C4H9
N
C4H9
H3C
N
N
OH
Cl
Cl
H
N
H
O
O
N
Dimroth Rearrangement
N
O
N
NH
H3C
H3C
NH
O
Cl
Cl
II
7b
Scheme 3. Postulated mechanism of the reaction.
3.5. Synthesis of various derivatives of
abstracting the proton of the hydroxyl group from I which subse-
quently attacks the nitrile group to give the cyclised intermediate II.
Intermediate II under the reaction conditions undergoes Dimroth
rearrangement to furnish the final product. The smooth conversion
of pyrano[3,2-c]piperidine derivative 5a and cyclohexanone into
piperido[3ꢀ,4ꢀ:5,6]pyrano[2,3-d]pyrimidinone 7b with high atom
economy via Pinner reaction and Dimroth rearrangement in the
presence of [BMIM]OH and absence of any other base suggests that
the BIL (basic ionic liquid) activates the hydroxyl group for the
nucleophilic attack and thus, expedites the reaction.
piperido[3ꢀ,4ꢀ:5,6]pyrano[2,3-d]pyrimidinone 7a–7o and 8a–8e
Under optimized conditions, we tried to survey the feasibil-
ity and scope of the strategy for which we synthesised a variety
of substituted pyrano[3,2-c]piperidine derivatives (5a-f) by using
variants of the aromatic aldehydes (2a-f), and we got very satisfac-
tory results with all variants (Table 4, entries 1–6). The aldehydes
with electron-withdrawing groups exerted a very positive response
towards the yield as well as the rate of the target product for-
mation (Table 4, entry 1–4), 4-chlorobenzaldehyde being the best
substituent (Table 4, entry 1). Identities of all the synthesised com-
pounds were confirmed by 1HNMR, 13CNMR, mass spectral data
and elemental analysis.
In an attempt to further analyse and extend the scope of the
strategy, we subjected a series of ketones to react with substrate,
i.e., pyrano[3,2-c]piperidine derivative 5a. The reaction proceeded
well in nearly all the ketones although the yields did vary because of
the steric strain imposed by some ketones (Table 5, entries 1–10).
The best yield was obtained with cyclohexanone (Table 5, entry
2). Encouraged by the results, we probed the reaction of 5a with a
range of aromatic aldehydes with electron-donating and electron-
withdrawing groups. All of these aldehydes performed well in the
reaction and furnished the pyrimidinone variants in good yields
(Table 5, entries 11–15).
3.3. Effect of pH of basic compounds as catalyst in the reaction
The effect of pH of basic compounds as catalyst in the reaction
medium was studied. The results have been summarized in Table 2.
The basic ionic liquid [BMIM]OH with pH 9.37 gave the best yields
(Table 2, entry 6). The other basic ionic liquids with pH comparable
to [BMIM]OH also did not prove very satisfactory for the reaction.
Table 2
Effect of pH of basic catalysts on the reaction.a
Entry
Base + solvent
pH
12.24
>14
13.92
13.33
12.67
Product yield
1
2
3
4
5
DBU + MeOH
DBU + CH3CN
DBU + DMF
DBU + [BMIM]Br
DBU + [BMIM]Cl
24
–
37
40
44
3.6. Synthesis of piperido[3ꢀ,4ꢀ:5,6]pyrano[2,3-d]pyrimidinone (7
and 8) derivatives using oil bath heating and its comparison with
microwave-assisted reaction
Ionic liquidsb
6
7
8
[BMIM]OH
[BMIM]Im
[DBU]Ac
[C8DABCO]NTf2
9.37
10.11
10.50
9.09
93
54
41
–
For comparison purposes, all the reactions were also carried out
in a thermostated oil-bath at the same temperature for optimized
period of time. The results have been summarised in Table 6. The
results in Table 6 clearly show a significant reduction in the yields
of the product in case of reactions carried out in oil bath. Further,
the time required for the reactions to reach the reported yield was
quite high. This observation clearly indicates the existence of a non
9
10
2-[2-
11.24
15
(Dimethylamino)ethoxy]ethyl-
N,N-diisopropylammonium
bis(trifluoromethanesulfonyl)imide
a
Temperature = 34 ◦C.
Solvent–water, concentration of base = 10%.
b

I.R. Siddiqui et al. / Journal of Molecular Catalysis A: Chemical 382 (2014) 126–135
131
Table 4
Synthesis of piperido[3ꢀ,4ꢀ:5,6]pyrano[2,3-d]pyrimidinone derivatives using cyclohexanone (6b) and various substituted pyrano[3,2-c] piperidine analogues (5a-g).
O
CN
O
R1
R1
O
H2C
H
N
R1-CHO
(2)
[BMIM]OH
rt (10) min
O
CN
R1
R1
O
NH2
CN
(4)
(6b)
[BMIM] OH
MW
N
NH
N
N
H3C
[BMIM]OH
rt (1.5 h)
N
H3C
O
R1
R1
CH3
CH3
1
3
5
7 and 8
Entry
R1CHO
Pyrano-piperidines
Product
Time (min)
Yielda (%)
Cl
Cl
CHO
Cl
H
N
O
NH2
O
N
NH
N
1
10
93
H3C
CN
H C
3
O
2a
2b
7b
5a
Cl
O
Cl
O2N
O2N
CHO
NO2
H
O
NH2
CN
N
N
N
NH
2
10
91
H3C
H3C
O
8a
5b
NO2
NO2
S
S
N
H
N
O
O
NH2
CN
O
S
3
10
83
NH
N
2c
H3C
H3C
O
S
S
8b
5c
N
N
CHO
H
N
O
N
NH2
CN
O
N
N
NH
4
N
10
87
H3C
H3C
N
O
2d
8c
5d
CHO
H
N
O
NH2
CN
O
5
10
80
N
N
NH
H3C
H3C
O
2e
8d
5e
H C
3
H3C
CHO
H
N
O
NH
2
O
N
N
NH
H C
3
CN
6
15
70
H3C
O
CH3
2f
8e
CH
CH 3
3
5f
a
Isolated yields after purification.

132
I.R. Siddiqui et al. / Journal of Molecular Catalysis A: Chemical 382 (2014) 126–135
Table 5
Basic ionic liquid catalyzed synthesis of piperido[3ꢀ,4ꢀ: 5,6]pyrano[2,3-d]pyrimidinone derivatives using 5a and various carbonyl compounds.a
O
R1
R1
H
N
R2
R3
O
R2
O
NH2
CN
R3
(6)
N
NH
N
H3C
[BMIM] OH
MW(10-18 min)
H3C
R1
O
R1
5
7 and 8
Entry
Ketone/aldehyde
Product
Time (min)
Yieldb (%)
Cl
H
N
O
O
N
NH
1
18
70
H3C
O
6a
7a
Cl
Cl
H
N
O
O
N
NH
2
10
93
H C
3
O
6b
7b
Cl
Cl
H
O
O
N
N
N
N
N
NH
3
15
85
H3C
H3C
H3C
H3C
O
6c
7c
Cl
O
Cl
H
N
O
NH
4
5
6
15
15
15
84
82
82
6d
O
7d
Cl
O
Cl
H
N
O
NH
6e
O
7e
Cl
O
Cl
H
N
O
NH
6f
O
7f
Cl

I.R. Siddiqui et al. / Journal of Molecular Catalysis A: Chemical 382 (2014) 126–135
133
Table 5 (Continued )
Entry
Ketone/aldehyde
Product
Time (min)
Yieldb (%)
Cl
H
O
N
O
N
NH
7
12
89
H3C
H3C
H3C
H3C
6g
O
7g
Cl
O
Cl
Cl
Cl
H
N
O
N
N
N
NH
NH
NH
8
15
15
15
80
83
90
O
6h
7h
Cl
O
H
N
O
9
O
6i
7i
Cl
O
H
N
N
O
10
N
O
6j
7j
7k
7l
Cl
O
Cl
H
N
O
N
NH
11
15
91
H3C
O
6k
Cl
O
Cl
Cl
H
N
O
N
NH
12
15
88
H3C
Cl
O
6l
Cl

134
I.R. Siddiqui et al. / Journal of Molecular Catalysis A: Chemical 382 (2014) 126–135
Table 5 (Continued )
Entry
Ketone/aldehyde
Product
Time (min)
Yieldb (%)
Cl
F
H
O
N
O
6m
N
NH
13
15
85
H3C
F
O
7m
Cl
Cl
CH3
H
N
O
O
N
NH
14
15
90
H3C
H3C
6n
O
7n
Cl
Cl
OCH3
H
O
N
O
N
NH
15
15
90
H3C
H3CO
6o
O
7o
Cl
a
Reaction conditions:pyrano[3,2-c]piperidine derivative 5a (1.0 mmol), carbonyl compound 6a-o (1.3 mmol), [BMIM]OH (2 mL).
Isolated yields after filtration and purification.
b
Table 6
4. Conclusions
Conventional vs. microwave conditions.
In conclusion, our strategy using a BIL presents an efficacious
and convenient procedure for the synthesis of novel substituted
pyrimidinone ring systems having piperidine, pyran and pyrimidi-
none rings fused together without the need of any toxic catalyst
or solvent. We report for the first time the synthesis of this novel
potentially bioactive heterocyclic scaffold. The synthetic strategy
offers marked improvements with regards to reaction rate, reac-
tion time, yields of the product, greenness of procedure, avoidance
of the use of toxic bases and thus, it offers an effective methodology
for the synthesis of novel fused pyrimidinone derivatives. How-
ever, most conspicuously, this strategy demonstrates the catalytic
effect of basic IL [BMIM]OH on the intramolecular Pinner reaction
between hydroxyl group and nitrile group. Discernibly, this pro-
cedure can be used effectively for the synthesis of diverse fused
pyrimidinone libraries.
Product
Classical conditionsa
(thermo stated oil
bath)
Microwave irradiationa
Time (h)
Yieldb (%)
Time (min)
Yieldb (%)
7a
7b
6
5
42
60
15
10
70
93
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
8a
8b
8c
8d
8e
6
5
6
7
6
7
6
6
7
7
6
6
7
5
6
5
5
6
47
43
40
40
48
41
44
48
50
42
46
49
47
52
48
49
44
40
15
15
15
15
12
15
15
15
15
15
15
15
15
10
10
10
10
15
85
84
82
82
89
80
83
90
91
88
85
90
90
91
83
87
80
70
Acknowledgements
Authors gratefully acknowledge the financial support by CSIR,
New Delhi, UGC, New Delhi and are thankful to SAIF, Chandigarh
for spectral analysis.
a
Reaction conditions: pyrano[3,2-c]piperidine derivative 5a (1.0 mmol), carbonyl
compound 6a-o (1.3 mmol), [BMIM]OH (2 mL).
Appendix A. Supplementary data
b
Isolated yields after filtration and purification.
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.molcata.
2013.10.026.
thermal microwave effect. It is thus assumed that the microwave-
ionic liquid synergy plays a significant role in the reaction and it
combines with the specific effect of the electromagnetic field of the
microwaves in decreasing the activation energy of the reaction by
stabilising the polar activated complex of the reaction, to provide
excellent yields in short reaction times.
References
[1] (a) K.S. Atwal, G.C. Rovnyak, B.C. O’Reillu, J. Schwartz, J. Org. Chem. 54 (1989)
5898–5907;

I.R. Siddiqui et al. / Journal of Molecular Catalysis A: Chemical 382 (2014) 126–135
135
(b) C.O. Kappe, W.M.F. Fabian, M.A. Semones, Tetrahedron 53 (1997)
2803–2816;
[12] H. Hoffmann, M. Nuchter, B. Ondruschka, P. Wasserscheid, Green Chem. 5
(2003) 296–299.
(c) Y. Zhu, S. Huang, Y. Pan, Eur. J. Org. Chem. (2005) 2354–2367;
(d) H.M. Gaber, M.C. Bagley, S.M. Sheriff, U.M. Abdul-Raouf, J. Het. Chem. 47
(2012) 1162–1170.
[13] J.M. Levenque, G. Cravotto, Chimia (Aarau) 60 (2006) 613–620.
[14] (a) J.A. Boon, S.A. Levinsky, J.L. Pflig, J.S. Wilker, J. Org. Chem. 51 (1986) 480–483;
(b) R. Sheldon, Chem. Commun. (2001) 2399–2407;
[2] (a) G.L. Anderson, J.L. Shim, A.D. Broom, J. Org. Chem. 41 (1976) 1095;
(b) E.M. Griva, S. Lee, C.W. Siyal, D.S. Duch, C.A. Nichol, J. Med. Chem. 23 (1980)
327–329.
[3] M.M. Ghorab, A.A. Hassan, Y. Phosphorus, Sulfur Silicon Relat. Elem. 141 (1998)
257–261.
[4] (a) D. Heber, C. Heers, U. Ravons, Pharmazie 48 (1993) 537;
(b) S. Furuya, T. Ohtaki, Eur. Pat. Appl. EP. 608565, Chem. Abstr. 121 (1994)
205395.
[5] C.J. Shishoo, V.S. Shirsath, I.S. Rathod, V.P. Yande, Eur. J. Med. Chem. 35 (2000)
351–358.
(c) A.L. Zhu, T. Jiang, D. Wang, B.X. Han, L. Liu, J. Huang, Z.C. Zhang, D.H. Sun,
Green Chem. 7 (2005) 514–517;
(d) Y.S. Kim, R.S. Varma, Tetrahedron Lett. 46 (2005) 7447–7449;
(e) B.C. Ranu, R. Jana, J. Org. Chem. 70 (2005) 8621–8624.
[15] (a) P. Formentin, H. Garcia, A. Levya, J. Mol. Catal. A: Chem. 214 (2004) 237;
(b) H. Chen, D.R. Justes, R.G. Cooks, Org. Lett. 7 (2005) 3949–3952.
[16] B.C. Ranu, S. Banerjee, Org. Lett. 7 (2005) 3049–3052.
[17] C.R. Brindaban, R. Jana, S.J. Sowmiah, Org. Chem. 72 (2007) 3152–3154.
[18] (a) J.M. Xu, B.K. Liu, W.B. Wu, C. Qian, Q. Wu, X.F. Lin, J. Org. Chem. 71 (2006)
3991–3993;
[6] W.J. Coater, Eur. Pat. 351058, Chem. Abstr. 113 (1990) 40711.
[7] N. Kitamura, A. Onishi, Eur. Pat. 163599, Chem. Abstr. 104 (1984) 186439.
[8] (a) C. Mohan, V. Kumar, P.M. Mahajan, Tetrahedron Lett. 45 (2004) 6075–6077;
(b) Z. Li-Jun, Y. Xi-quan, L. Jia-Rong, S. Da-Xin, Z. Ling, F. Yan-Qiu, Chin. J. Str.
Chem. 27 (2008) 1469–1474;
(b) L.D.S. Yadav, S. Singh, V.K. Rai, Tetrahedron Lett. 50 (2009) 2208–2212.
[19] (a) I.R. Siddiqui, P.K. Singh, J. Singh, J. Singh, J. Agric. Food Chem. 51 (2003)
7062–7065;
(b) I.R. Siddiqui, S.A. Singh, P.K. Singh, V. Srivastava, J. Singh, Arkivoc XII (2008)
277–285;
(c) H. Zhang, Z. Zhou, Z. Yao, F. Xu, Q. Shen, Tetrahedron Lett. 50 (2009)
1622–1624;
(c) I.R. Siddiqui, A. Singh, S. Shamim, S. Srivastava, P.K. Singh, S. Yadav, R.K.P.
Singh, Synthesis 10 (2010) 1613–1616;
(d) R.N. Bhattacharya, K. Pradip, M. Gourhari, Tetrahedron Lett. 52 (2011)
26–28.
(d) I.R. Siddiqui, S. Shamim, A. Singh, V. Srivastava, S. Yadav, Arkivoc XI (2010)
232–241;
[9] (a) S. Mashkouri, M.R. Naimi-Jamal, Molecules 14 (2009) 474–479;
(b) J. Pandey, N. Anand, R.P. Tripathi, Tetrahedron 65 (2009) 9350–9356;
(c) M.C. Parlato, C. Mugnaini, M.L. Renzulli, F. Corell, M. Botta, Arkivoc V (2004)
349–363.
[10] (a) L. Perreux, A. Loupy, Tetrahedron 57 (2001) 9199–9283;
(b) P. Lidstrom, J. Tierney, B. Wathey, J. Westman, Tetrahedron 57 (2001)
9225–9283;
(d) I.R. Siddiqui, S. Shamim, D. Kumar, Shireen, M.A. Waseem, New J. Chem. 36
(2012) 2209–2214;
(e) I.R. Siddiqui, Shireen, S. Shamim, A.H. Abumhdi, M.A. Waseem, A. Srivas-
tava, Rahila, A. Srivastava, New J. Chem. (2013), http://dx.doi.org/10.1039/
C3NJ41070F.
[20] L.F. Xiao, Q.F. Yue, C.G. Xia, L.W. Xu, J. Mol. Catal. A: Chem. 279 (2008) 230–234.
[21] J. Shen, H. Wang, H. Liu, Y. Sun, Z. Liu, J. Mol. Catal. A: Chem. 280 (2008) 24–28.
[22] C. Xuewei, L. Xuehui, S. Hongbing, L. Yangxiao, W. Furong, H. Aixi, Chin. J. Catal.
29 (2008) 957–959.
[23] A.G. Ying, L. Liu, G.F. Wu, G. Chen, X.Z. Chen, W.D. Ye, Tetrahedron Lett. 50
(2009) 1653–1657.
[24] (a) M. Hut’ka, S. Toma, Monatsh Chem. 140 (2009) 1189–1194;
(b) C. Paun, J. Barklie, P. Goodrich, H.Q.N. Gunaratne, A. McKeowna, V.I.
Pârvulescu, C. Hardacre, J. Mol. Catal. A: Chem. 269 (2007) 64–71.
[25] J.M. Xu, C. Qian, B.K. Liu, Q. Wu, X.F. Lin, Tetrahedron 63 (2007) 986–990.
[26] M.A.P. Martins, E.A. Guarda, C.P. Frizzo, E. Scapin, P. Beck, A.C. da Costa, N.
Zanatta, H.G. Bonacorso, J. Mol. Catal. Chem. 266 (2007) 100–103.
[27] (a) A. Aggarwal, N.L. Lancaster, A.R. Sethi, T. Welton, Green Chem. 4 (2002)
517–520;
(c) C.O. Kappe, Angew. Chem. Int. Ed. 43 (2004) 6250–6284;
(d) M. Larhed, Microwaves in Organic Synthesis, 2nd ed., Wiley-VCH, GmbH &
KGaA, Weinheim, 2006;
(e) E. Gershonov, E. Katz, Y. Karton, Y. Zafrani, Tetrahedron 63 (2007)
3762–3767;
(f) S. Caddick, R. Fitzmaurice, Tetrahedron 65 (2009) 3325–3355.
[11] (a) T. Welton, Chem. Rev. 99 (1999) 2071–2083;
(b) L.A. Blanchard, D. Hancu, E.J. Becman, J.F. Brennecke, Nature 399 (1999)
28–29;
(c) P.J. Wasserscheid, W. Keim, Angew. Chem. Int. Ed. 39 (2000) 3772–3789;
(d) R.A. Brown, P. Pollet, E. Mckoon, C.A. Eckert, C.L. Liotta, D.G. Jessop, J. Am.
Chem. Soc. 123 (2001) 1254–1255;
(e) X.F. Yang, M.W. Wang, C.J. Li, Org. Lett. 5 (2003) 657–660;
(f) W. Leitner, Nature 423 (2003) 930–931;
(g) A. Kumar, S.S. Pawar, J. Org. Chem. 69 (2004) 1419–1420.
(b) J. Ross, J.L. Xiao, Chem. Eur. J. 9 (2003) 4900–4906.
[28] (a) J.M. Xu, C. Qian, B.-K. Liu, Q. Wu, X.F. Lin, Tetrahedron 63 (2007) 986–990;
(b) H. Sun, D. Zhang, F. Wang, C. Liu, J. Phys. Chem. 111 (2007) 4535–4541.