One-pot, three-component condensation reaction in water: An efficient and improved procedure for the synthesis of pyran annulated heterocyclic systems

Article abstract of DOI:10.1080/00397910601039242

Environmentally friendly three-component condensation reactions of an activated C-H acid, an aldehyde, and alkyl nitriles to afford the corresponding pyran annulated heterocyclic systems in water in good yields, avoiding the addition of any catalyst, are reported. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910601039242

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One‐Pot, Three‐Component Condensation
Reaction in Water: An Efficient and Improved
Procedure for the Synthesis of Pyran
Annulated Heterocyclic Systems
Ahmad Shaabani a , Sima Samadi, a & Abbas Rahmati a
a Department of Chemistry, Shahid Beheshti University, Tehran, Iran
Version of record first published: 06 Feb 2007.
To cite this article: Ahmad Shaabani , Sima Samadi, & Abbas Rahmati (2007): One‐Pot, Three‐Component
Condensation Reaction in Water: An Efficient and Improved Procedure for the Synthesis of Pyran Annulated
Heterocyclic Systems, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 37:3, 491-499
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Synthetic Communicationsw, 37: 491–499, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910601039242
One-Pot, Three-Component Condensation
Reaction in Water: An Efficient and
Improved Procedure for the Synthesis of
Pyran Annulated Heterocyclic Systems
Ahmad Shaabani, Sima Samadi, and Abbas Rahmati
Department of Chemistry, Shahid Beheshti University, Tehran, Iran
Abstract: Environmentally friendly three-component condensation reactions of an
activated C-H acid, an aldehyde, and alkyl nitriles to afford the corresponding pyran
annulated heterocyclic systems in water in good yields, avoiding the addition of any
catalyst, are reported.
Keywords: 1,3-dimethylbarbituric acid, 4-hydroxycoumarin, 4-hydroxy-6-methyl-
pyrone, pyran annulated heterocyclic system, three-component reaction, water
INTRODUCTION
Although synthesis of organic compounds in the nature occurs very efficiently
in water, organic chemists have traditionally been taught that water is not
generally a good solvent for carrying out synthetic reactions. Nevertheless,
in recent years reports have appeared in increasing number describing use
of water as a solvent for various organic reactions.[1–3]
An important example of the significant rate enhancements, which
sparked much interest in the use of water as a solvent, was the finding by
Breslow that the reaction between cyclopentadiene and butanone was more
than 700 times faster in water than in many organic solvents.[4] Breslow
Address correspondence to Ahmad Shaabani, Department of Chemistry, Shahid
Beheshti University, P. O. Box 19396-4716, Tehran, Iran. E-mail: a-shaabani@cc.
sbu.ac.ir
491

492
A. Shaabani, S. Samadi, and A. Rahmati
explained his results on the basis of hydrophobic interactions that induce a
favorable aggregating of the polar components in the polar water.[5]
Further reasons that make water unique compared to other organic
solvents are that it is inexpensive, nonflammable, and naturally occurring;
has a high specific heat capacity; and more importantly, is not toxic. Choice
of solvent is one of the problems to face to perform eco-efficient processes.
Pyrano[2,3-d]-, pyrido[2,3-d]pyrimidines, and pyrano[3,2-c]benzopyran
have attracted much attention owing to their biological activities. A number
of methods have been reported for the synthesis of these compounds in the
presence of organic bases such as piperidine or pyridine in an organic
solvent (i.e., ethanol, methanol, pyridine); however, most of these rely on
multistep reactions and complex synthetic pathways, have long reaction
times, and have low yields.[6–20]
Recently, the one-pot synthesis of pyran annulated heterocyclic systems
from condensation of 4-hydroxycoumarin[18] or 4-hydroxy-6-methylpyrone[18]
or 1,3-dimethylbarbituric acid[19] with relatively expensive reagents such as
dimethyl acetylenedicarboxylate and isocyanide has been reported in toxic
benzene under reflux conditions. In addition, a new method based on a
multi-component reaction strategy using microwave heating in the solid
state has been presented.[20] Nevertheless, the use of a green solvent such as
water, which shows both economical and synthetic advantages, is desirable.
As a part of our research to develop a green chemistry by one-pot
uncatalyzed synthesis of target molecules in water alone as the reaction
medium,[21–23] we report here the three-component condensation reactions of
4-hydroxycoumarin 3a, 4-hydroxy-6-methylpyrone 3b, 1,3-dimethylbarbituric
acid 3c, 1,3-dimethyl-6-amino uracil 3d, or dimedone 3e with p-substituted
benzaldehydes 1 and alkyl nitriles 2 for the preparation of pyran annulated
heterocyclic systems without using any catalysts in water at 808C (Scheme 1).
Because of hydrophobic interaction behavior that generates an internal
pressure and promotes the association of the reagents in a solvent cavity
during the activation process, water showed an acceleration of the three-
component reactions in comparison to organic solvent. The results for
various pyran annulated heterocyclic systems are summarized in Table 1.
It is important to note that the separation and purification processes are very
simple, as they involve only Buchner funnel filtration and washing with water.
It is interesting that the reaction easily occurs in water although the
mechanism involves a net dehydration of the alcoholic intermediates
obtained by nucleophilic attack of the active methylene of 2 to the carbonyl
group of 1; the ease of the dehydration process is ascribable to the extent of
C55C double bond conjugation in the Knoevenagel condensation product.
Other authors have also previously found similar unexpected solvent
effects.[24–26]
We have not established a mechanism for the formation of pyran
annulated heterocyclic systems, but a reasonable possibility is indicated in
Scheme 2.

Pyran Annulated Heterocyclic Systems
493
Scheme 1.
The reaction presumably proceeds in two steps: condensation of aldehyde 1
and alkyl nitrile 2 by standard Knoevenagel reaction produces 3-benzylidene-
2,4-pentanedione 5.[27] Then C-H acid 3e is reacted with compound 5
through a Michael addition, produces product type 6, and after cyclization
affords pyran annulated heterocyclic system 4j.[28]
To explore the scope and limitations of this reaction further, we have
extended it to various para-substituted benzaldehydes in the presence of
active C-H acids. As indicated in Table 1, the reaction proceeds efficiently
with benzaldehyde and electron-withdrawing and electron-releasing para-
substituted benzaldehydes.
CONCLUSION
In summary, the one-pot, three-component uncatalyzed conversion of activated
C-H compounds such as 4-hydroxycoumarin, 4-hydroxy-6-methylpyrone,

Table 1. One-pot synthesis of pyran annulated heterocyclic systems in water at 808C
MP (8C)
Activated C-H
reactant
Entry
Product
Yield (%)
77
Time (h)
9.5
Found
Reported
4a
265–267
273–275[6]
4b
4c
4d
4e
70
69
63
65
10
7.5
10
237–239
258–260
240–243
230–233
—
—
—
10.5
236–238[15]

4f
61
66
11
205–208
210–213
205–207[15]
4g
9.5
216–218[15]
4h
81
11
206–208
210–212[20]
4i
4j
62
72
8.5
8.5
290–293
229–231
308–309[20]
233–234[29]

496
A. Shaabani, S. Samadi, and A. Rahmati
Scheme 2.
1,3-dimethylbarbituric acid, 1,3-dimethyl-6-amino uracil or dimedone, with
p-substituted benzaldehydes and alkyl nitriles, to pyran annulated hetero-
cyclic systems has been efficiently performed in water as a green solvent.
The one-pot nature, the use of water as an ecocompatible reaction solvent,
and the easy separation of products make it an interesting alternative to
the reported approaches.[18–20]
EXPERIMENTAL
Melting points were measured on an Electrothermal 9100 apparatus and are
uncorrected. Mass spectra were recorded on a Finnigan-MAT 8430 mass spec-
trometer operating at an ionization potential of 70 eV. IR spectra were
1
recorded on a Shimadzu IR-470 spectrometer. H and 13C NMR spectra
were recorded on a Bruker DRX-300 Avance spectrometer at 300.13 and
75.47 MHz, respectively. NMR spectra were obtained on solutions in
DMSO-d6. All the products are known compounds (except 4b, 4c, and 4d),
1
which were characterized by IR, H NMR, and mass spectral data, and their
melting points were compared with literature reports.
Typical Procedure for the Preparation of 4a
The mixture of malononitrile (0.066 g, 1 mmol) and benzaldehyde (0.106 g,
1 mmol) in 20 ml of distilled water was stirred for 3 h at 808C. The reaction

Pyran Annulated Heterocyclic Systems
497
mixture was cooled, and 4-hydroxycoumarin (0.162 g, 1 mmol) was added in
small portions. Stirring was continued at 808C for 9.5 h. The progress of
reaction was monitored on thin-layer chromatography (TLC). After com-
pletion of the reaction, the reaction mixture was cooled to room temperature,
and the resulting yellow precipitated was filtered and washed with water
(50 ml). The solid residue (yellow crystals) was dried and crystallized from
Et2O or acetone to yield 4a (0.243 g, 77%).
Data
2-Amino-3-cyano-4-(phenyl)-4H,5H-pyrano[3,2-c]benzopyran-5-one (4a):
Light yellow crystals. Mp 265–2678C. IR (KBr) n: 3370 (NH2), 2190 (CN),
1
1701 (C55O) cm21. H NMR (acetone-d6) d 4.56 (s, CH, 1H), 6.66 (br s,
NH2, 2H), 7.25–8.00 (m, arom. 9H) ppm. MS m/z (%): 316 (Mþ, 15), 249
(100), 221 (21), 163 (15), 121 (28), 92 (69).
2-Amino-3-cyano-4-(40-methoxyphenyl)-4H,5H-pyrano[3,2-c]benzopyran-
5-one (4b): Yellow crystals. Mp 237–2398C. IR (KBr) n: 3365 (NH2), 2185
1
(CN), 1702 (C55O) cm21. H NMR (DMSO-d6) d 3.72 (s, OCH3, 3H), 4.40
(s, CH, 1H), 6.87–7.90 (m, arom. 8H and NH2, 2H) ppm. 13C NMR
(DMSO-d6) d 36.7, 55.5, 58.7, 104.7, 113.5, 114.3, 117.0, 119.8, 122.9,
125.1, 129.2, 133.3, 135.9, 152.5, 153.6, 158.4, 158.8, 160.0 ppm. MS m/z
(%): 346 (Mþ, 10), 280 (100), 249 (80), 184 (59), 162 (25), 120 (30).
2-Amino-3-cyano-4-(40-nitrophenyl)-4H,5H-pyrano[3,2-c]benzopyran-
5-one (4c): Yellow crystals. Mp 258–2608C. IR (KBr) n: 3275 (NH2), 2180
1
(CN), 1703 (C55O). H NMR (DMSO-d6) d 4.67 (s, CH, 1H), 7.45–8.19
(m, arom. 8H, and NH2, 2H) ppm; 13C NMR (DMSO-d6) d 37.2, 57.2,
103.2, 113.3, 117.1, 119.4, 123.0, 124.2, 125.2, 129.6, 133.6, 147.0,
151.2, 152.7, 154.4, 158.5, 160.0 ppm. MS m/z (%): 362 (Mþ, 47), 345
(15), 296 (40), 278 (100), 248 (83), 92 (85).
2-Amino-3-carboethoxy-4-(40-nitrophenyl)-4H,5H-pyrano[3,2-c]benzo-
pyran-5-one (4d): Yellow crystals. Mp 240–2438C. IR (KBr) n: 3430
(NH2), 1714 (C55O). 1H NMR (CDCl3): d 1.16 (t, 3J ¼ 7.11 Hz, CH3,
3
3H), 4.08 (q, J ¼ 7.11 Hz, CH2, 2H), 5.03 (s, CH, 1H), 6.56 (br s, NH2,
2H), 7.33–8.13 (m, arom. 8H) ppm. 13C NMR (CDCl3) d 14.2, 35.8,
60.2, 106.4, 113.1, 117.0, 122.3, 123.4, 124.3, 124.6, 129.5, 132.7, 146.7,
151.7, 152.7, 153.6, 158.0, 160.5, 168.2 ppm. MS m/z (%): 408 (Mþ, 2),
335 (25), 286 (100), 240 (90), 121 (40), 92 (25).
2-Amino-3-cyano-7-methyl-4-(phenyl)-4H-pyrano[4,3-b]pyran-5-one (4e):
Yellow crystals. Mp 230–2338C. IR (KBr) n: 3300 (NH2), 2190 (CN), 1706
(C55O). H NMR (acetone-d6) d 2.25 (s, CH3, 3H), 4.38 (s, CH, 1H), 6.17
1

498
A. Shaabani, S. Samadi, and A. Rahmati
(s, C55CH, 1H), 6.40 (br s, NH2, 2H), 7.23–7.32 (m, arom. 5H) ppm. MS m/z
(%): 281 (M þ 1, 52), 280 (Mþ, 50), 203 (100), 171 (10), 102 (38), 43 (52).
2-Amino-3-cyano-7-methyl-4-(40-methoxyphenyl)-4H-pyrano[4,3-b]pyran-
5-one (4f): Yellow crystals; Mp 205–2088C. IR (KBr) n: 3320 (NH2), 2275 (CN),
1700 (C55O). 1H NMR (DMSO-d6) d 2.21 (s, CH3, 3H), 3.72 (s, OCH3, 3H), 4.22
(s, CH, 1H), 6.26 (s, C55CH, 1H), 6.84–7.16(m, arom. 5HandNH2, 2H)ppm. MS
m/z (%): 310 (Mþ, 75), 279 (10), 243 (90), 203 (90), 145 (55), 117 (30), 43 (100).
2-Amino-3-cyano-7-methyl-4-(40-nitrophenyl)-4H-pyrano[4,3-b]pyran-5-one
(4g): Yellow crystals. Mp 210–2138C. IR (KBr) n: 3390 (NH2), 2190 (CN), 1701
(C55O). H NMR (DMSO-d6) d 2.23 (s, CH3, 3H), 4.51 (s, CH, 1H), 6.32
1
3
(s, C55CH, 1H), 7.36 (br s, NH2, 2H), 7.51 (d, 2H, J ¼ 8.03 Hz, C6H4NO2),
3
8.19 (d, 2H, J ¼ 8.03 Hz, C6H4NO2) ppm. MS m/z (%): 325 (Mþ, 25), 301
(10), 273 (30), 242 (40), 203 (75), 43 (100).
7-Amino-6-cyano-1,3-dimethyl-5-(phenyl)-1,5-dihydro-pyrano[2,3-d] pyri-
midine-2,4-dione (4h): White crystals. Mp 206–2088C. IR (KBr) n: 3300
(NH2), 2195 (CN), 1710 (C55O). H NMR (DMSO-d6) d 3.07 (s, CH3, 3H),
1
3.36 (s, CH3, 3H), 4.31 (s, CH, 1H), 7.24–7.34 (m, arom. 5H, and NH2, 2H)
ppm. MS m/z (%): 311 (Mþ, 23), 243 (100), 186 (33), 131 (16).
7-Amino-6-cyano-1,3-dimethyl-5-(phenyl)-1H-pyrido[2,3-d]pyrimidine-2,4-
dione (4i): White crystals. Mp 290–2938C. IR (KBr) n: 3350 (NH2), 2195 (CN),
1710 (C55O). H NMR (DMSO-d6) d 3.06 (s, CH3, 3H), 3.49 (s, CH3, 3H),
1
7.21–7.43 (m, arom. 5H, and NH2, 2H) ppm. MS m/z (%): 306 (Mþ, 100),
249 (16), 222 (10), 194 (52), 165(10), 140 (28).
2-Amino-3-cyano-7,7-dimethyl-4-phenyl-4,6,7,8-tetrahydro-chromen-5-
one (4j): White crystals. Mp 229–2318C. IR (KBr) n: 3390 (NH2), 2190 (CN),
1
1675 (C55O). H NMR (CDCl3) d 1.04 (s, CH3, 3H), 1.12 (s, CH3, 3H), 2.22
(2 ꢀ d, AB system, 2J ¼ 16.40, CHAHB, 2H), 2.45 (s, CH2, 2H), 4.40 (s, CH,
1H), 4.58 (br s, NH2, 2H), 7.17–7.32 (m, arom. 5H) ppm. MS m/z (%): 293
(28), 217 (100), 161 (35), 133 (25), 102 (20), 77 (25), 39 (45).
ACKNOWLEDGMENT
We gratefully acknowledge the financial support from the Research Council
of Shahid Beheshti University.
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