A novel light induced Knoevenagel condensation of Meldrum's acid with aromatic aldehydes in aqueous ethanol

Article abstract of DOI:10.1016/j.tetlet.2011.03.123

A highly efficient environment-friendly photochemical methodology has been developed for the condensation of Meldrum's acid with aromatic aldehydes in water-ethanol solution sans any catalyst, support or promoter.

Full text of DOI:10.1016/j.tetlet.2011.03.123

Tetrahedron Letters 52 (2011) 2869–2872
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Tetrahedron Letters
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A novel light induced Knoevenagel condensation of Meldrum’s acid
with aromatic aldehydes in aqueous ethanol
⇑
Somnath Ghosh , Jhantu Das, Subhagata Chattopadhyay
Department of Chemistry, Jadavpur University, Kolkata 700 032, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly efficient environment-friendly photochemical methodology has been developed for the conden-
sation of Meldrum’s acid with aromatic aldehydes in water–ethanol solution sans any catalyst, support or
promoter.
Received 12 February 2011
Revised 21 March 2011
Accepted 24 March 2011
Available online 1 April 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Photochemical Knoevenagel condensation
Aromatic aldehydes
Meldrum’s acid
Aqueous ethanol
The use of Meldrum’s acid (2,2-dimethyl-1,3-dioxan-4,6-dione),
prepared by Meldrum1 in 1908, as an active methylene compound
was utilized after about 40 years of its preparation, when David-
son2 in 1948 correctly assigned its structure along with the posi-
tion of acidic hydrogen onto the central carbon atom.
Interestingly, its high acidity is still an attractive area of study as
evidenced by the recent works of Fillion et al.3 It is well known that
Meldrum’s acid can undergo Knoevenagel condensation with alde-
hydes and ketones (as imines) in an efficient fashion and excellent
reviews4 have been published. The various condensing agents that
have been employed are sodium hydroxide,5 pyridine,2,6 piperi-
dine/glacial acetic acid,7 metal salts8,9 ionic liquid,10 triethyl
ammonium formate,11 piperidinium acetate,12 anhydrous zinc
chloride,13 neutral alumina,14 kaolin,15 and clays16 in different sol-
vents17 such as DMF or DMSO and under varied experimental con-
ditions like microwave irradiation,18 ultrasound exposure,7 and
melt reaction,19 and also in solid phase.20 Additionally, uncatalyzed
reactions in water/water-surfactant21 have also been reported. It is
noteworthy to observe that all these protocols have been accom-
plished under thermal reaction conditions and disposal of toxic
solvents and catalysts often pose a problem.
the realm of photochemical reactions24 has prompted us to envis-
age a hitherto unknown visible light induced uncatalyzed and
unsupported photochemical Knoevenagel condensation of the title
compound with various aromatic aldehydes in water–ethanol mix-
ture (1:1 v/v) and also under microwave condition over neutral
alumina (Scheme 1) and we wish to report here our observations.
The photochemical reactions were found to be very clean and
the products were obtained in extremely pure crystalline states
with an average yield of 76–92%. In general, the products were iso-
lated by simple filtration and needs no further crystallization. On
the other hand, the microwave assisted reaction, accomplished in
an average time period of 30–150 s in the temperature range of
81–181 °C, products were isolated by column chromatography
and required further crystallization from appropriate solvents with
yield varying from 55% to 78%; and the results of these experi-
ments are given in Table 1. It appears that the microwave reactions
are better than the light induced reactions, but so far as the isola-
tion and purity of the products (3) are concerned, the photochem-
ical reactions are more efficient though, the time required is more
than the microwave assisted reactions.
Furthermore, by this novel photochemical methodology, cou-
marin-3-carboxylic acid, a potent bioactive substance,25 useful as
a fluorescent probe26,27 and triplet sensitizer,28,29 has been synthe-
sized in almost analytically pure form and in amazingly high yield
(Scheme 2).
In conclusion, we have developed a potentially efficient, abso-
lutely clean and very high yielding eco-friendly methodology30 in
neutral aqueous ethanol solution for the condensation of Mel-
drum’s acid with aromatic aldehydes devoid of any unwarranted
In order to perform organic reactions in environment-friendly
conditions, photochemical reactions particularly using visible light
are an attractive area of study and more so, if these reactions are
done in water or water–ethanol mixtures; and generally consid-
ered as a clean and green procedure.22,23 Our enduring interest in
⇑
Corresponding author. Tel.: +91 033 2414 6223; fax: +91 033 2414 6223.
E-mail address: ghoshsn@yahoo.com (S. Ghosh).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.123

2870
S. Ghosh et al. / Tetrahedron Letters 52 (2011) 2869–2872
O
O
O
O
Ar
O
aq. ethanol (1:1) / hν
Ar-CHO
O
O
O
MW / neutral Al2O3
1
3
2
H
O
H
OMe H
H
MeO
MeO
O
O
O
O
O
,
,
,
d:
a:
MeO
b:
c:
MeO
Ar =
,
Cl
H
H
H
H
H
HO
g:
O
O
,
,
,
,
e:
O2N
f:
h:
O
O
i:
OH
Scheme 1. Photochemical Knoevenagel condensation between aromatic aldehydes and Meldrum’s acid.
Table 1
Results of Photochemical Knoevenagel condensation of aromatic aldehydes and Meldrum’s acid
Entry
Substrate
Producta
Yieldb (%) [lit.18c yield (%)]
Mp (°C)
Time (min)
15
H
O
O
O
O
O
A (h
m): 92
1
127
B (MW): 74[90]
MeO
MeO
O
3a
O
O
1a
H
MeO
MeO
MeO
MeO
O
A (h
m): 88
2
3
4
171
140
156
10
15
15
B (MW): 77[99]
O
3b
O
O
1b
OMe H
OMe
A (h
m): 88
O
B (MW): 67
MeO
MeO
O
O
1c
H
3c
O
O
A (h
m): 90
O
O
B (MW): 56[91]
Cl
Cl
O
3d
1d
H
H
O
O
O
A (h
B (MW): 55[83]
m): 76
5
6
7
217–18
10
15
20
O2N
O2N
O
O
O
1e
3e
A (h
B (MW): 75
m): 89
O
O
109
O
O
1f
3f
H
O
HO
HO
O
O
A (h
B (MW): 58
m): 79
170–71
O
O
1g
3g

S. Ghosh et al. / Tetrahedron Letters 52 (2011) 2869–2872
2871
Table 1 (continued)
Entry
Substrate
Producta
Yieldb (%) [lit.18c yield (%)]
Mp (°C)
Time (min)
H
O
O
O
O
O
A (h
B (MW): 78[89]
m): 87
8
91–92
15
20
O
O
O
1h
3h
H
COOH
O
A (h
B (MW): 56
m): 89
9
192
O
3i
OH
1i
a
All products were characterized by their satisfactory spectral data and also by comparison with literature data (vide Supplementary data).
Yield refers to combined amounts of first and second crops of products obtained either from aqueous ethanol (Method A) or after chromatography (Method B).
b
O
H
O
O
O
O
O
aq. ethanol (1:1) / hν
O
..
O
O
OH
OH
MW / neutral Al2O3
1i
2
CH3COCH3
COOH
O
COO
O
-H / + H
O
O
H
3i
Scheme 2. Photochemical Knoevenagel condensation of salicylaldehyde and Meldrum’s acid.
8. Fildes, D.; Caignaert, V.; Villemin, D.; Jaffres, P. A. Green Chem. 2001, 3, 52–56.
9. Bandgar, B. P.; Uppalla, L. S.; Sadavarte, V. S. J. Chem. Res., Synop. 2002, 40–41.
10. Hu, Y.; Wei, P.; Huang, H.; Le, Z.-G.; Chen, Z.-C. Synth. Commun. 2005, 35, 2955–
2960.
side reactions such as Norrish Type I cleavage in the absence of any
catalyst, support or promoter and may be considered as an excel-
lent improvement over the existing methods.
11. Mudhar, H.; Witty, A. Tetrahedron Lett. 2010, 51, 4972–4974.
12. Song, A.; Wang, X.; Lam, K. S. Tetrahedron Lett. 2003, 44, 1755–1758.
13. Rao, P. S.; Venkatratnam, R. V. Indian J. Chem. 1993, 32B, 484.
14. Villemin, D. Chem. Ind. 1983, 478–479.
Acknowledgments
15. Thorat, M. T.; Jagdale, M. H.; Mane, R. B.; Salunkhe, M. M.; Wadagaonkar, P. P.
Curr. Sci. 1987, 56, 771–772.
Financial assistance is provided to one of the authors (J.D.) from
UGC, Govt. of India. Also partial funding from DST-PURSE and CAS,
Department of Chemistry, Jadavpur University is acknowledged.
16. Bandgar, B. P.; Uppalla, L. S.; Kurule, D. S. Green Chem. 1999, 1, 243–245.
17. (a) Hedge, J. A.; Kruse, C. W.; Snyder, H. R. J. Org. Chem. 1961, 26, 3166–3170;
(b) Shi, D. Q.; Wang, Y. C.; Lu, Z. S.; Dai, G. Y. Synth. Commun. 2000, 30, 713–726.
18. (a) Abdallah-El, A. S.; Texier-Boulet, F.; Hamelin, J. Synthesis 1994, 258–260; (b)
Huang, Z. Z.; Wu, L. L.; Huang, X. Hecheng Huaxue 1998, 6, 184; (c) Chakrabarty,
M.; Mukherjee, R.; Chakrabarty, M.; Arima, S.; Harigaya, Y. Lett. Org. Chem.
2006, 3, 868–871.
19. Kaupp, G.; Naimi-Jamal, M. R.; Schmeyers, J. Tetrahedron 2003, 59, 3753–3760.
20. Watson, B. T.; Christiansen, G. E. Tetrahedron Lett. 1998, 39, 6087–6090.
21. Bigi, F.; Carloni, S.; Ferrari, L.; Maggi, R.; Mazzacani, A.; Sartori, G. Tetrahedron
Lett. 2001, 42, 5203–5205.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.03.123.
References and notes
22. Hoffmann, N. Chem. Rev. 2008, 108, 1052–1053.
23. Fagnoni, M.; Dondi, D.; Ravelli, D.; Albini, A. Chem. Rev. 2007, 107, 2725–2756.
24. Ghosh, S. N.; Das, J. Tetrahedron Lett. 2011, 52, 1112–1116. and references cited
therein.
25. Murray, R. D. H.; Mendez, J.; Brown, S. A. The Natural Coumarins: Occurrence,
Chemistry and Biochemistry; John Wiley & Sons: New York, 1982.
26. Khalfan, H.; Abuknesha, R.; Rand-Weaver, M.; Price, R. G.; Robinson, D.
Histochem. J. 1986, 18, 497–499.
1. Meldrum, A. N. J. Chem. Soc. 1908, 93, 598–601.
2. Davidson, D.; Bernhard, S. A. J. Am. Chem. Soc. 1948, 70, 3426–3428.
3. (a) Dumas, A. M.; Fillion, E. Acc. Chem. Res. 2010, 43, 440–454; (b) Fillion, E.;
Wilsily, A.; Fishlock, D. J. Org. Chem. 2009, 74, 1259–1267; (c) Nakamura, S.;
Hirao, H.; Ohwada, T. J. Org. Chem. 2004, 69, 4309–4316; (d) Lee, I.; Han, I. S.;
Kim, C. K.; Lee, H. W. Bull. Korean Chem. Soc. 2003, 24, 1141–1149; (e) Byun, K.;
Mo, Y.; Gao, J. J. Am. Chem. Soc. 2001, 123, 3974–3979.
4. Reviews: (a) McNab, H. Chem. Soc. Rev. 1978, 7, 345–358; (b) Tietze, L. F.;
Beifuss, U. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Heathcock, C. H., Eds.; Pergamon: Oxford, England, 1991; Vol. 2, p 341; (c)
Chen, B.-C. Heterocycles 1991, 32, 529–597.
27. Peroni, E.; Caminati, G.; Baglioni, P.; Nuti, F.; Chelli, M.; Papini, A. M. Bioorg.
Med. Chem. Lett. 2002, 12, 1731–1734.
28. Specht, D. P.; Martic, P. A.; Farid, S. Tetrahedron 1982, 38, 1203–1211.
29. Williams, J. L. R.; Specht, D. P.; Farid, S. Polym. Eng. Sci. 1983, 23, 1022–1024.
30. Method A: An equimolar quantity of Meldrum’s acid (2) (10 mmol) and
different aromatic aldehydes (1a–i) were taken in aqueous-ethanol mixture
(20 mL, 1:1 proportion) and irradiated with a 150 W tungsten lamp (Philips
India Ltd.). The reaction time varied on an average from 10 to 20 min for
different aromatic aldehydes (monitored by TLC after 5 min interval). Upon
5. Shirokava, E. A.; Segal, G. M.; Torgov, I. V. Bioorg. Khim. 1988, 14, 236–242.
6. Corey, E. J. J. Am. Chem. Soc. 1952, 74, 5897–5905.
7. (a) Scuster, P. O.; Polansky, E.; Wessely, F. Monatsch. Chem. 1964, 95, 53–58; (b)
Kraus, G. A.; Krolski, M. E. J. Org. Chem. 1986, 51, 3347–3350.

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S. Ghosh et al. / Tetrahedron Letters 52 (2011) 2869–2872
completion of the reaction, the reaction mixture was cooled and the crystalline
product (3a–i) were isolated by a column filtration over silica gel (petroleum
ether, 60–80 °C and ethyl acetate, 10–40% v/v) in pure form.
product (3a–i) so obtained was filtered, washed, with water and dried in vacuo.
The Knoevenagel condensation products were isolated in high yields in
essentially pure form.
Method B: Aromatic aldehydes (1a–i) (10 mmol), Meldrum’s acid (2) (10 mmol)
and neutral alumina (2 g) were mixed well with the help of a mortar pestle and
the mixture was subjected to microwave irradiation (2450 MHz) at
temperatures 81 °C (for 30 s, entries 2 and 3), 103 °C for 1 min 10 s, entry 8),
131 °C (for 50 s, entries 1 and 6), 142 °C (for 1 min, entry 9),154 °C (for 1 min
20 s, entry 7), 181 °C (for 2 min 30 s, entries 4 and 5), and the condensation
5-(2,4-Dimethoxy-benzylidene)-2,2-dimethyl-[1,3]
Yellow shining flakes, Yield: 88% (h ), mp 140 °C; IR (KBr) mmax 2998, 2943,
2835, 1750, 1728, 1604, 1579 cmÀ1 1H NMR (300 MHz, CDCl3, 22 °C) d 8.86 (s,
dioxane-4,6-dione
(3c):
m
;
1H), 8.43 (d, J = 9.0 Hz, 1H), 6.56 (d, J = 9.0 Hz, 1H), 6.42 (s, 1H), 3.90 (s, 6H),
1.79 (s, 6H) ppm; 13C NMR (75 MHz, CDCl3, 22 °C) d 166.6, 164.0, 162.7, 160.8,
152.1, 135.5, 114.6, 110.2, 105.7, 103.8, 97.5, 55.8, 55.6, 27.4 ppm. Anal. Calcd
for C15H16O6: C, 61.64; H, 5.52. Found: C, 61.52; H, 5.42.