A heterogeneous strong basic Mg/La mixed oxide catalyst for efficient synthesis of polyfunctionalized pyrans

Article abstract of DOI:10.1016/j.tetlet.2008.02.154

An efficient synthesis of polyfunctionalized 4H-pyrans is carried out in one pot through condensation of an aldehyde, malononitrile, and an active methylenic diketo compound using a heterogeneous strong basic Mg/La mixed oxide catalyst. The protocol offer

Full text of DOI:10.1016/j.tetlet.2008.02.154

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2730–2733
A heterogeneous strong basic Mg/La mixed oxide catalyst
for efficient synthesis of polyfunctionalized pyrans
N. Seshu Babu, Nayeem Pasha, K. T. Venkateswara Rao, P. S. Sai Prasad, N. Lingaiah *
Catalysis Laboratory, I&P C Division, Indian Institute of Chemical Technology, Hyderabad, India
Received 4 December 2007; revised 25 February 2008; accepted 28 February 2008
Available online 2 March 2008
Abstract
An efficient synthesis of polyfunctionalized 4H-pyrans is carried out in one pot through condensation of an aldehyde, malononitrile,
and an active methylenic diketo compound using a heterogeneous strong basic Mg/La mixed oxide catalyst. The protocol offers
advantages in terms of higher yields, short reaction times, and mild reaction conditions, with reusability of the catalyst.
Ó 2008 Published by Elsevier Ltd.
Keywords: Pyrans; Mg/La mixed oxide; Three component reaction; Diketo esters
1. Introduction
and ultrasonic irradiation.9 In addition, the one-pot
synthesis of 4H-pyrans has been reported using TMG-
[bmim][X] and [2-aemim][PF6] as catalysts under
microwave irradiation.10,11 A few reports exist in the liter-
ature using organic bases12–14 as catalysts, for example,
tetrabutylammonium bromide, (S)-proline, rare earth
perfluorooctanoates, and hexadecyltrimethylammonium
bromide for the synthesis of 4H-pyrans in one-pot
reactions. All of these catalysts have merits, while some
are disadvantaged by limitations such as harsh reaction
conditions, low yields, tedious work-ups, and poor recycl-
ability. Thus, the development of a suitable solid base cata-
lyst for the efficient synthesis of 4H-pyrans in a single step
still remains an attractive goal to researchers. From both
economical and environmental point of views, the use of
nontoxic solvents and nonmetallic catalysts is very promis-
ing. In the past few years, the synthesis of solid base cata-
lysts derived from alkali earth metallic precursors has
played a prominent role in the field of heterogeneous cata-
lysis. Solid base catalysts have several advantages over
homogeneous organic basic catalysts, such as easy recovery
of the catalyst, simple product isolation, and recyclability.
Thus, the heterogeneous solid base catalysts have been
recognized as potential alternatives to homogeneous
organic basic catalysts.
The synthesis of polyfunctionlized 4H-pyrans group is
attractive to researchers as it is a constituent of various nat-
ural products.1,2 The main interest in the 4H-pyran group
is due to its biological and pharmacological3 activities.
These compounds are used as anti-coagulants, anticancer
agents, spasmolytics, anti-anaphylactics, etc.4,5 The phar-
macological activities exhibited by these compounds are
mainly due to the presence of different heterocyclic ring
systems. Generally, 5-substituted-2-amino-4-aryl-3-cyano-
6-methyl-4H-pyrans are prepared from arylidenemalono-
nitriles and activated methylene compounds in the presence
of organic bases.6,7 Moreover, these compounds can be
used in various applications as cognitive enhancers for
the treatment of neuro degenerative diseases, including
Alzheimer’s disease, as well as for the treatment of schizo-
phrenia and myoclonus. Also a number of 2-amino-4H-
pyran derivatives are useful as photoactive materials.8
Thus, in view of their wide utility, researchers have synthe-
sized the 4H-pyran unit using different methods including
radiative and non-radiative techniques such as microwave
*
Corresponding author. Tel.: +91 40 27193163; fax: +91 40 27160921.
E-mail address: nakkalingaiah@iict.res.in (N. Lingaiah).
0040-4039/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2008.02.154

N. Seshu Babu et al. / Tetrahedron Letters 49 (2008) 2730–2733
2731
In an effort to design various solid base catalysts for the
4. Catalyst characterization methods
synthesis of polyfunctionalized pyran derivatives, we have
identified that the Mg/La catalyst efficiently catalyzes the
one-pot condensation of an aldehyde, malononitrile, and
a ketoester (Scheme 1). Mg/La mixed oxide catalysts are
reusable basic catalysts, and the presence of La enhances
the basicity of the catalyst. The Mg/La mixed oxides are
used as catalysts for various organic transformations.15–20
The present catalyst leads to 4H-benzopyran derivatives
in high yields within short reaction times at the reflux tem-
perature of methanol. To the best of our knowledge, this is
the first heterogeneous strong basic Mg/La catalyst for the
synthesis of 4H-pyrans under mild reaction conditions.
The physical properties of the Mg/La catalyst were stud-
ied by X-ray diffraction, temperature programmed desorp-
tion (TPD) of CO2 to determine the total basicity of the
catalyst and by Brunauer, Emmett, Teller (BET) surface
area measurements. These results are provided in Supple-
mentary data.
The Mg/La catalyst was studied along with other known
solid base catalysts using the reaction of 4-chlorobenzalde-
hyde, malononitrile, and ethyl acetoacetate in 2 mL of
methanol as a model system for the synthesis of the corre-
sponding 4H-pyrans. The results are summarized in Table
1. The results show that the three component reactions
catalyzed by commercial MgO and KF/Al2O3 proceed in
longer reaction times and afforded moderate product
yields. The Mg–Al hydrotalcite and Mg–Al–CO3 catalysts
exhibited good activity requiring a 3–4 h reaction time. It
is interesting to note that the Mg/La catalyst catalyzes
the present reaction in high yield within a short reaction
time compared to the other solid base catalysts. It appears
that the basicity of the catalyst plays a prominent role. In
the literature,15–20 it has been reported that the Mg/La
catalyst possesses strong basic sites compared to other solid
base catalysts. The presence of La2O3 in proximity to MgO
leads to enhanced basicity. The presence of strong basic
sites in the Mg/La catalyst was confirmed by CO2 TPD
measurements (see Supplementary data). The presence of
a strong CO2 desorption peak at high temperature (ꢀTmax
600–700 °C) in the CO2 TPD profile indicates the presence
of strong basic sites.
2. Preparation of the Mg/La catalyst
The Mg/La catalyst was prepared by a co-precipitation
method while maintaining the pH of the solution at pH 10.
In a typical method, 10.55 g of Mg(NO3)2 and 4.45 g of
La(NO3)3 (corresponding to a Mg/La molar ratio of 3:1)
were dissolved in 500 ml of water. The solution was preci-
pitated by adding a mixture of 1 M KOH and 0.25 M
K2CO3 as a precipitating agent at a constant pH of 10.
After the completion of precipitation, the catalyst solution
was washed several times with deionized water and filtered.
The obtained catalyst was dried at 120 °C for 12 h and
finally calcinated at 650 °C for 4 h.
3. Catalytic activity measurements
In a typical experiment 0.05 g of catalyst was added to a
mixture of 140 mg of p-benzaldehyde (1 mmol), 72.6 mg of
malononitrile (1.1 mmol), and 143 mg of ethyl acetoacetate
(1.1 mmol) in 2 mL of methanol. The reaction mixture was
stirred under reflux and the progress of the reaction was
monitored by TLC. After completion, the catalyst was sep-
arated from the reaction mixture by centrifugation. The
excess methanol was removed by evaporation and the
resultant 4H-pyran derivative was isolated by column
chromotagraphy. The structure of the compound was
determined by 1H NMR spectroscopy and the results were
comparable with the reported data.
The present method was extended to various aldehydes
1, malononitrile 2, and several active methylene compo-
nents 3 in the presence of a catalytic amount of Mg/La
to give the desired pyrans21 4. The results are presented
in Table 2 and indicate that aldehydes bearing electron-
withdrawing groups react more quickly than their
Table 1
Synthesis of benzopyran 4 using various solid base catalystsa
Ar
Ar
The separated catalyst was washed with methanol and
dried at 120 °C for 2 h. The dried catalyst was reused for
the recycling experiments.
O
O
H
O
CN
1
Catalyst
EtO
CN
EtO
+
Methanol
Reflux
O
NH2
Me
CN
O
Me
2
3
4
Ar = 4-ClC6H4
R1
R1
Entry
Catalyst
Time (h)
Yield 4 (%)
O
O
H
O
CN
Mg/La mixed oxide
1
1
2
3
4
5
a
MgO (commercial)
KF/Al2O3
Mg–Al (hydrotalcite)
Mg–Al–CO3
5
5
3
4
1
67
74
82
64
92
CN
EtO
EtO
R2
Methanol
+
R2
º
65 C
O
NH2
CN
O
4
2
3
Mg–La mixed oxide
Scheme 1. Synthesis of polyfunctionalized 4H-pyrans via one-pot con-
densation of an aldehyde, malononitrile, and ethyl acetoacetate using Mg/
La mixed oxide.
Reaction conditions: 4-chlorobenzaldehyde (1 mmol); malononitrile
(1.1 mmol); ethyl acetoacetate (1.1 mmol); temperature 65 °C; yields were
determined by 1H NMR spectroscopy.

2732
N. Seshu Babu et al. / Tetrahedron Letters 49 (2008) 2730–2733
Table 2
reaction by abstracting a proton from the active methylene
component. As a result, an alkene intermediate may form
with the aldehyde. This in turn reacts with 1,3-diethyl
acetone dicarboxylate/ethyl acetoacetate/diethyl malonate
via Michael addition to give the polyfunctionalized
4H-pyrans 4.
In summary, an efficient heterogeneous strong basic
Mg/La catalyst is reported for the synthesis of 4H-pyran
derivatives in a three component condensation reaction
of an aldehyde, malononitrile, and a ketoester. Advantages
of the strategy include simple catalyst preparation, mild
reaction temperature, easy recovery, and reusability of
the catalyst with consistent activity and short reaction
times.
Mg/La catalyzed synthesis of 4H-pyrans derivativesa
R1
R1
O
O
O
H
O
CN
Mg/La mixed oxide
Methanol
1
CN
EtO
EtO
R2
+
º
R2
65 C
NH2
CN
O
Entry
R1
Ph
R2
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
Me
1
83
88
86
92, 89c
90
79
87
82
60
52
35
87
76
4-NO2-C6H4
3-NO2-C6H4
4-Cl–C6H4
Me
Me
Me
1
1
1
4-CN–C6H4
4-OH–C6H4
4-Me–C6H4
4-OMe–C6H4
4-CH3-COO–C6H4
CH3-CH2
Me
Me
Me
Me
Me
Me
1
2
1.5
1.5
3
Acknowledgment
10
11
12
13
14
15
a
3
One of the authors K.T.V. thanks CSIR, New Delhi,
for the award of junior research fellowship.
4-TBDMSO–C6H4
4-Cl–C6H4
4-Me–C6H4
4-OH–C6H4
C6H5
Me
1.5
1
1
1.5
1.5
CH2COOEt
CH2COOEt
CH2COOEt
OEt
15
78
Supplementary data
Reaction conditions: aldehyde derivative (1 mmol); malononitrile
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2008.02.154.
(1.1 mmol); active methylene diketo compound (1.1 mmol).
b
Yields were determined by 1H NMR spectroscopy.
Yield obtained after the fourth recycle.
c
References and notes
electron-donating aldehyde counterparts. For example,
aromatic aldehydes such as 4-chloro, 4-nitro, 3-nitro, and
4-cyano benzaldehydes (entries 2–5) react quickly with high
product yields in comparison to 4-hydroxy, 4-methyl, 4-
methoxy, and 4-acetoxy benzaldehyde derivatives22 (entries
6–9). The catalyst also exhibited good activity with an ali-
phatic aldehyde (entry 10). The present catalyst was also
studied by varying the active methylenic derivative22
(entries 12–15). Recycling experiments were performed
using the Mg/La catalyst for the synthesis of 5-ethoxy-
carbonyl-2-amino-4-(4-chlorophenyl)-3-cyano-6-methyl-4H-
pyran (Table 2, entry 4). These recycling experiments show
that the Mg/La catalyst catalyzes the reaction with consis-
tent activity even after four cycles.
1. Hatakeyama, S.; Ochi, N.; Numata, H.; Takano, S. J. Chem. Soc.,
Chem. Commun. 1988, 17, 1202.
2. Gonzalez, R.; Martin, N.; Seoane, C.; Marco, J. L.; Albert, A.; Cano,
F. H. Tetrahedron Lett. 1992, 33, 3809.
3. Green, G. R.; Evans, J. M.; Vong, A. K. In Comprehensive
Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven,
E. F. V., Eds.; Pergamon Press: Oxford, 1995; Vol. 5, p 469.
4. Foye, W. O.; Prinicipi di Chemico Farmaceutica, Piccin, Padova,
Italy, 1991, p 416.
5. Bonsignore, L.; Loy, G.; Secci, D.; Calignano, A. Eur. J. Med. Chem.
1993, 28, 517.
6. Martin, N.; Pascual, C.; Seoane, C.; Soto, J. L. Heterocycles 1987, 26,
2811.
7. Quintela, J. M.; Peinador, C.; Moreira, M. J. Tetrahedron 1995, 51,
5901.
The mechanism of the present reaction (Scheme 2)
initially proceeds by Knoevenagel condensation, as the
catalyst possesses strong basic sites, which promotes the
8. Armesto, D.; Horspool, W. M.; Martin, N.; Ramos, A.; Seaone, C. J.
Org. Chem. 1989, 54, 3069.
9. Zhou, J. F.; Tu, S. J.; Gao, Y.; Ji, M. Chin. J. Org. Chem. 2001, 21,
742.
10. Peng, Y.; Song, G. Catal. Commun. 2007, 8, 111.
11. Fotouhi, L.; Heravi, M. M.; Fatehi, A.; Bakhtiari, K. Tetrahedron
Lett. 2007, 48, 5379.
R1
O
O
CN
Mg/La mixed oxide
Methanol, Reflux
O
12. Jin, T. S.; Xiao, J. C.; Wang, S. J.; Li, T. S.; Song, X. R. Synlett 2003,
2001.
13. Balalaie, S.; Bararjanian, M.; Amani, A. M.; Movassagh, B. Synlett
2006, 263.
14. Jin, T. S.; Wang, A. Q.; Wang, X.; Zhang, J. S.; Li, T. S. Synlett 2004,
871.
15. Veldurthy, B.; Clacens, J.-M.; Figueras, F. Adv. Synth. Catal. 2005,
347, 767.
16. Kantam, M. L.; Kochkar, H.; Clacens, J.-M.; Veldurthy, B.; Garcia-
Ruiz, A.; Figueras, F. Appl. Catal. B 2005, 55, 177.
17. Veldurthy, B.; Clacens, J.-M.; Figueras, F. J. Catal. 2005, 229, 237.
18. Veldurthy, B.; Figueras, F. Chem. Commun. 2004, 734.
EtO
EtO
EtO
CN
1
R-CHO
+
R2
+
O
NH2
R2
3
4
CN
1
2
Knoevengel
O
R1
O
R1
O
R1
CN
CN
CN
Michael addition
EtO
CN
R2
O
NC
CN
R2
Scheme 2. A plausible mechanism of 4H-pyran synthesis.

N. Seshu Babu et al. / Tetrahedron Letters 49 (2008) 2730–2733
2733
19. Cwik, A.; Hell, Z.; Figueras, F. Adv. Synth. Catal. 2006, 348,
523.
(q, 2H), 5.71 (br s, 2H); 13C NMR (400 MHz, CDCl3, ppm): d 13.96,
14.18, 31.89, 41.18, 46.39, 60.33, 61.57, 110.62, 114.80, 146.08, 165.93,
168.43; ESI-MS m/z 236 (M+); CHNS analysis: C, 61.3; H, 7.1; N,
11.2.
5-Ethoxycarbonyl-2-amino-4-(4-(tert-butyldimethylsilyloxy)phenyl)-3-
cyano-6-methyl-4H-pyrans (Table 2, entry 11): Mp: 141–142 °C; 1H
NMR (400 MHz, DMSO-d6, ppm) d 0.15 (s, 6H), 1.01 (s, 9H), 1.18 (t,
3H), 2.28 (s, 3H), 2.28 (s, 3H), 3.44 (br s, 2H), 4.04 (q, 2H), 4.22 (s,
1H), 6.76 (d, 2H), 7.01 (d, 2H); 13C NMR (400 MHz, DMSO-d6,
ppm): d À4.03, 14.27, 18.42, 26.04, 38.58, 59.93, 61.28, 112.86, 114.63,
120.11, 128.95, 138.32, 154.36, 156.62, 166.01, 168.95; ESI-MS m/z
414 (M+); CHNS: C, 63.65, H, 7.4, N, 7.1.
20. Cwik, A.; Hell, Z.; Figueras, F. Org. Biomol.Chem. 2005, 3, 4307.
21. The new compounds were analyzed by 1H NMR, 13C NMR, ESI-MS,
and elemental (CHNS) analysis. 5-Ethoxycarbonyl-2-amino-4-(4-
acetoxyphenyl)-3-cyano-6-methyl-4H-pyrans (Table 2, entry 9): Mp:
216–217 °C; 1H NMR (400 MHz, DMSO-d6, ppm) d 1.033 (t, 3H).
2.24 (s, 3H), 3.37 (s, 3H), 3.96 (q, 2H), 4.30 (s, 1H), 6.95 (br s, 1H),
7.07 (d, 2H), 7.15 (d, 2H); 13C NMR (400 MHz, DMSO-d6, ppm) d
14.27, 18.75, 21.38, 38.78, 57.58, 60.78, 107.67, 120.27, 122.32, 128.72,
142.91, 149.74, 157.37, 159.06, 165.94, 169.77; ESI-MS m/z: 342 (M+);
CHNS analysis: C, 63.5; H: 5.4, N, 8.2.
5-Ethoxycarbonyl-2-amino-4-ethyl-3-cyano-6-methyl-4H-pyrans (Ta-
ble 2, entry 10): Mp: 185–186 °C; 1H NMR (400 MHz, CDCl3, ppm) d
1.14 (t, 3H), 1.28 (t, 3H), 2.61 (s, 3H), 3.52 (m, 2H), 3.72 (t, 1H), 4.14
22. Lingaiah, B. P. V.; Venkat Reddy, G.; Yakaiah, T.; Narsaiah, B.;
Reddy, S. N.; Yadla, R.; Shantan Rao, P. Synth. Commun. 2004, 34,
4431.