Efficient synthesis of pyrano[3,2-c]pyridines via a green and catalyst-free method at ambient temperature, and related DFT calculations

Article abstract of DOI:10.1007/s00706-012-0851-0

Twelve medicinally important pyrano[3,2-c]pyridine derivatives were precipitated, with high yields, from ethanol solutions of malononitrile and (E)-3,5-bis(benzylidene)-4-piperidones at ambient temperature, requiring almost no work-up. Natural bond order calculations at the B3LYP/6-31+G*level indicate that electron-withdrawing groups on the phenyl rings deplete electron density on β-atoms (with respect to the carbonyl groups) of the piperidones, leading to higher yields of the corresponding products with shorter reaction times. This green methodology appears in a clear contrast to all previous reports, where either a catalyst and/or microwave was employed. So, simplicity and short reaction time, non-toxicity of the solvent, as well as economic feasibility are major advantages of this chemically waste-free process.

Full text of DOI:10.1007/s00706-012-0851-0

Monatsh Chem (2013) 144:703–706
DOI 10.1007/s00706-012-0851-0
ORIGINAL PAPER
Efficient synthesis of pyrano[3,2-c]pyridines via a green
and catalyst-free method at ambient temperature,
and related DFT calculations
•
Shahnaz Rostamizadeh M. Z. Kassaee
•
•
Nasrin Shadjou Hassan Zandi
Received: 25 January 2012 / Accepted: 23 August 2012 / Published online: 18 October 2012
Ó Springer-Verlag 2012
Abstract Twelve medicinally important pyrano[3,2-c]pyr-
idine derivatives were precipitated, with high yields, from
ethanol solutions of malononitrile and (E)-3,5-bis(benzyli-
dene)-4-piperidones at ambient temperature, requiring almost
no work-up. Natural bond order calculations at the B3LYP/6-
31?G*level indicatethatelectron-withdrawinggroupsonthe
phenyl rings deplete electron density onb-atoms (with respect
to the carbonyl groups) of the piperidones, leading to higher
yields of the corresponding products with shorter reaction
times. This green methodology appears in a clear contrast to
all previous reports, where either a catalyst and/or microwave
was employed. So, simplicity and short reaction time, non-
toxicity of the solvent, as well as economic feasibility are
major advantages of this chemically waste-free process.
Introduction
Environmentally benign methods for syntheses of phar-
maceutically and industrially important compounds are in
great demand [1]. Elimination of solvents in chemical
processes or performing reactions in eco-friendly solvents
such as water and ethanol are procedures of choice for
diminishing the environmental hazards of chemical reac-
tions [2].
Pyrano[3,2-c]pyridine derivatives are important heterocy-
clic compounds with a broad range of biological, medicinal,
and pharmacological properties. Some of them are constitu-
ents of antitumor, anti-inflammatory, and antifungal
compounds [3, 4]. In viewof these usefulproperties, a number
of preparative methods have been reported for the synthesis of
these molecules. El-Subbagh et al. [3, 5, 6] reported the
preparationofpyrano[3,2-c]pyridine derivatives throughtwo-
component reactions between a,b-unsaturated ketones and
malononitrile in refluxing BuOH. Microwave irradiation in
the presence of DMF solvent was reported by Han et al. [7, 8].
Also, these compounds have been synthesized via sodium
ethoxide catalysis under solvent-free conditions [9], or in
methanol containing sodium [10], or by hexadecyltrimethyl-
ammonium bromide in aqueous media and 110 °C [11], or by
KF-Al2O3 [12], as well as in sodium hydroxide or piperidine
under microwave irradiation [13].
Keywords Pyrano[3,2-c]pyridine ꢀ Catalyst free ꢀ
Ambient temperature ꢀ (E)-3,5-Bis(benzylidene)-
4-piperidones ꢀ Malononitrile ꢀ DFT calculations
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-012-0851-0) contains supplementary
material, which is available to authorized users.
S. Rostamizadeh (&) ꢀ N. Shadjou
Most of these protocols are time-consuming and demand
either classical thermal reaction conditions or microwave
irradiation and require disposal of toxic solvents and/or
catalysts. Hence, following our desire to adopt more eco-
nomical and efficient reaction conditions [14–17], herein
we report a green and catalyst-free synthesis of pyrano-
[3,2-c]pyridine derivatives 1a–1m through reactions
between malononitrile (2) and (E)-3,5-bis(benzylidene)-4-
piperidones 3 in ethanol at room temperature.
Department of Chemistry, K. N. Toosi University
of Technology, P.O. Box 15875-4416, Tehran, Iran
e-mail: rostamizadeh@kntu.ac.ir; shrostamizadeh@yahoo.com
M. Z. Kassaee
Department of Chemistry, Tarbiat Modares University,
Tehran, Iran
H. Zandi
Department of Chemistry, Islamic Azad University,
Shahre-Rey Branch, Tehran, Iran
123

704
S. Rostamizadeh et al.
All reactions proceeded smoothly and required just a
simple filtration to give pure 1a–1l. Interestingly 3m gave
only a trace of 1m (Table 2, entry 13), as a result of the
relatively lower charge on the b-atom caused by the
extended conjugation (Scheme 2).
Table 1 Effect of the solvent on the synthesis of 1e
Entry
Solvent
Reaction
conditions
Time/min
Yield/%
1
2
3
4
5
6
7
EtOH
r.t.
20
45
98
CH3OH
CH3CN
CH3CN
H2O/DMF
H2O
r.t.
83
Natural bond order (NBO) calculations at the B3LYP/
6-31?G* level indicated that electron-withdrawing groups
on the phenyl rings (Table 2, entries 1, 3–5, 9–12) deplete
electron density on the corresponding b-atoms compared to
electron-donating moieties (Table 2, entries 2, 6, 7). This
results in higher yields and shorter reaction times for 1a,
1c, 1d, 1e, 1i, 1j, 1k, and 1l than 1b, 1f, and 1g (Table 3).
In summary, an eco-friendly methodology was devel-
oped for the efficient synthesis of pyrano[3,2-c]pyridine
derivatives in ethanol at ambient temperature. NBO cal-
culations at the B3LYP/6-31?G* level indicate that
electron-withdrawing groups on the phenyl rings induce
greater charge on the b-atoms of 3, leading to higher yields
of the corresponding 1 with shorter reaction times.
r.t.
60
No reaction
Reflux
Reflux
Reflux
Reflux
150
30
40
80
240
300
No reaction
BuOH
65–97
[3, 5, 6]
8
DMF, NH4OAc
Microwave
7
95 [7]
Results and discussion
Our main objective was to develop an efficient, catalyst-
free, and simple method for the synthesis of pyrano[3,2-
c]pyridine derivatives 1 in a non-toxic solvent at room
temperature. Initially, we examined the reaction of 2 with
3e in different solvents including H2O/DMF, H2O, CH3CN,
CH3OH, and EtOH (Table 1; Scheme 1). At the first
glance, running the reaction in DMF/NH4OAc under
microwave irradiation seemed appealing because it gave
95 % yield of 1e in only 7 min (Table 1, entry 8) [7]. Yet,
such a procedure suffers from using an extra reagent
(NH4OAc) along with a toxic solvent (DMF) [18] as well
as employment of possibly harmful and/or rather expensive
electromagnetic waves. Consequently, EtOH was adopted
as the solvent of choice because it is green and gives 1e
with a high yield of 98 % in a reaction time of 20 min at
ambient temperature (Table 1, entry 1).
Experimental
Melting points were recorded on a Bu¨chi B-540 apparatus.
IR spectra were recorded on an ABB Bomem Model
1
FTLA200-100 instrument. H and 13C NMR spectra were
measured on a Bruker DRX-300 spectrometer, at 300 and
75 MHz, using TMS as an internal standard. Chemical
shifts (d) are reported relative to TMS, and coupling con-
stants (J) are reported in Hertz (Hz). Mass spectra were
recorded on a Shimadzu QP 1100 EX mass spectrometer
with 70-eV ionization potential. 3,5-Bis(benzylidene)-
4-piperidones 3 were synthesized according to [3].
Using similar conditions (Table 1, entry 1), we probed
substituent effects on this reaction by dissolving 2 in EtOH
and adding in turn 12 derivatives of 3 carrying either an
electron-donating or -withdrawing group on the phenyl ring
(Table 2). The latter groups afforded shorter reaction times
with higher yields of 1a, 1c, 1d, 1e, 1i, 1j, 1k, and 1l
(Table 2, entries 1, 3–5, 9–12). In contrast, longer reaction
times and lower yields were encountered for derivatives
with electron-donating groups: 1b, 1f, 1g (Table 2, entries
2, 6, 7).
General procedure for the synthesis of pyrano[3,2-c]-
pyridine derivatives
A mixture of 3,5-bis(benzylidene)-4-piperidone (0.33 mmol)
and malononitrile (0.33 mmol) in 5 cm3 ethanol was stirred at
room temperature for an appropriate period of time (Table 2).
After completion of the reaction (monitored by thin layer
chromatography; petroleum ether/EtOAc 2:1), the product
Scheme 1
NH2
CN
O
O
CN
CN
Solvent, r.t.
+
Cl
N
Cl
Cl
N
Cl
3e
2
1e
123

Synthesis of pyrano[3,2-c]pyridines
705
Table 2 Synthesis of pyrano[3,2-c]pyridines 3
NH2
CN
Ar
O
O
N
CN
Ar
Ar
Ar
+
CN
N
3
2
1
Entry
Product
Ar
Time/min
Yielda/%
M.p./°C
Lit. m.p./°C
References
1
1a
1b
1c
1d
1e
1f
2,3-Cl2-C6H3
25
[60
20
98
89
92
98
98
80
90
93
96
98
95
95
Trace
213–215
193–195
213–216
204–205
238–239
203–204
226–228
211–212
238–240
225–226
245–246
198–200
–
–
–
2
4-(C6H5CH2O)-C6H4
2-Cl-C6H4
–
–
3
208–210
197–198
238–240
203–204
215–217
200–202
238–240
225–227
245–246
199–200
–
[9]
[30]
[30]
[3]
[8]
[8]
[8]
[8]
[8]
[9]
[3]
4
4-F-C6H4
10
5
4-Cl-C6H4
20
6
4-CH3O-C6H4
4-CH3-C6H4
C6H5
60
7
1g
1h
1i
60
8
45
9
4-NO2-C6H4
3-NO2-C6H4
4-Br-C6H4
15
10
11
12
13
a
1j
10
1k
1l
30
2,4-Cl2-C6H3
2-Thienyl
25
1m
120
Isolated yields
Scheme 2
O
N
O
:
S
S
S
S
N
160.1 ppm; MS (EI): m/z (%) = 42 (100), 81 (46), 113
(30), 149 (70), 181 (60), 216 (53), 250 (91), 293 (12), 346
(11), 390 (14), 449 (19), 492 (22).
was collected and recrystallized from 95 % EtOH to give the
pure product.
(8E)-2-Amino-8-(2,3-dichlorobenzylidene)-4-(2,3-
dichlorophenyl)-5,6,7,8-tetrahydro-6-methyl-4H-
pyrano[3,2-c]pyridine-3-carbonitrile
(1a, C23H17Cl4N3O)
(8E)-2-Amino-8-[4-(benzyloxy)benzylidene]-4-[4-
(benzyloxy)phenyl]-5,6,7,8-tetrahydro-6-methyl-4H-
pyrano[3,2-c]pyridine-3-carbonitrile (1b, C37H33N3O3)
ꢀ
ꢀ
M.p.: 193-195 °C; IR (KBr): m = 3,388, 3,301, 2,182, 1,683,
M.p.: 213–215 °C; IR (KBr): m = 3,322, 3,260, 2,202,
1,642, 1,606 cm-1 1H NMR (300 MHz, DMSO-d6):
;
1
1,678, 1,637, 1,601 cm-1; H NMR (300 MHz, DMSO-
d = 2.13 (3H, s, N–CH3), 2.54 (1H, d, J = 14.4 Hz), 2.94
(1H, d, J = 14.0 Hz), 3.25 (1H, d, J = 14.4 Hz), 3.45 (1H, d,
J = 14.0 Hz), 3.97(1H, s, CH), 5.06(2H, s, OCH2), 5.10(2H,
s, OCH2), 6.75 (2H, s, NH2), 6.83 (1H, s, C=CH), 7.00 (2H,
d, J = 8.7 Hz), 7.03 (2H, d, J = 8.7 Hz), 7.12 (2H, d,
J = 8.7 Hz), 7.18 (2H, d, J = 8.7 Hz), 7.29–7.46 (10H, m)
ppm: 13C NMR (75 MHz, DMSO-d6): d = 44.4, 53.9, 54.4,
d6): d = 2.09 (3H, s, N–CH3), 2.51 (1H, d, J = 14.0 Hz),
3.02 (1H, d, J = 16.2 Hz), 3.15 (1H, d, J = 14.0 Hz), 3.31
(1H, d, J = 14.8 Hz), 4.7 (1H, s, CH), 6.94 (1H, s, C=CH),
7.05 (2H, s, NH2), 7.24–7.44 (4H, m), 7.58 (2H, d,
J = 8.0 Hz) ppm; 13C NMR (75 MHz, DMSO-d6):
d = 44.2, 53.7, 54.2, 118.8, 119.9, 128.0, 128.9, 129.2,
129.4, 129.6, 130.3, 130.6, 132.0, 136.3, 139.5, 142.7,
123

706
S. Rostamizadeh et al.
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6-31?G* level
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Compound
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C-10 and C-100
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3a
3b
3c
3d
3e
3f
-0.1483
-0.1526
-0.1461
-0.1404
-0.1455
-0.1629
-0.1564
-0.1473
-0.1433
-0.1435
-0.1531
-0.1496
-0.1788
98
89
92
98
98
80
90
93
96
98
95
95
Trace
3g
3h
3i
3j
3k
3l
3m
15. Rostamizadeh S, Amani AM, Mahdavinia GH, Sepehrian H,
Ebrahimia S (2009) Synthesis 1356
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130.9, 131.0, 132.3, 132.4, 139.1, 139.6, 139.7, 159.5, 159.6,
159.7, 162.8 ppm; MS (EI): m/z (%) = 42 (16), 65 (63), 91
(100), 131 (40), 174 (44), 198 (19), 222 (23), 250 (63), 382
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Gaussian 98 code [22–24] and an extra plus because of the
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the optimized structures was confirmed through the
development of the basis set B3LYP/6-31?G* [27, 28]. To
obtain natural charge data of atoms NBO calculations were
performed at the B3LYP/6-31?G* level [29].
Acknowledgments The authors gratefully acknowledge the Research
Council of K. N. Toosi University of Technology for financial support of
this work.
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