One-pot three-component reaction for the synthesis of pyran annulated heterocyclic compounds using DMAP as a catalyst

Article abstract of DOI:10.1016/j.tetlet.2011.08.019

The one-pot three-component reaction for the synthesis of pyran annulated heterocycles is reported by condensing aromatic aldehydes, ethyl cyanoacetate, or malononitrile and C-H activated acidic compounds in the presence of catalytic amount of 4-(dimethylamino)pyridine (DMAP) in ethanol under reflux conditions. The significant features of the present protocol are simple, environmentally benign, high yields, non-aqueous work-up procedure, no chromatographic separation and recyclability of the catalyst.

Full text of DOI:10.1016/j.tetlet.2011.08.019

Tetrahedron Letters 52 (2011) 5327–5332
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One-pot three-component reaction for the synthesis of pyran annulated
heterocyclic compounds using DMAP as a catalyst
⇑
Abu T. Khan , Mohan Lal, Shahzad Ali, Md. Musawwer Khan
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781 039, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The one-pot three-component reaction for the synthesis of pyran annulated heterocycles is reported by
condensing aromatic aldehydes, ethyl cyanoacetate, or malononitrile and C–H activated acidic com-
pounds in the presence of catalytic amount of 4-(dimethylamino)pyridine (DMAP) in ethanol under
reflux conditions. The significant features of the present protocol are simple, environmentally benign,
high yields, non-aqueous work-up procedure, no chromatographic separation and recyclability of the
catalyst.
Received 20 June 2011
Revised 31 July 2011
Accepted 2 August 2011
Available online 11 August 2011
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
Multicomponent reactions
Pyran annulated heterocyclic derivatives
4-Hydroxy-coumarin
4-(Dimethylamino)pyridine (DMAP)
Multicomponent reactions (MCRs) have gained considerable
attention due to powerful bond forming efficiency in combinatorial
and medicinal chemistry.1 The nature of the catalyst and sol-
vent2,3a also play a crucial role in the determination of the product
and selectivity. Therefore, development of an inexpensive, mild,
and reusable catalyst for MCRs remains of interest to the synthetic
organic chemist. We have demonstrated effectiveness of various
catalysts in organic synthesis using MCRs strategy.3 We conceived
that DMAP might be a better catalyst which can be explored fur-
ther for multicomponent reactions for the synthesis of pyran annu-
lated heterocycles. A few years ago, the importance and usefulness
of 4-(dimethylamino)pyridine (DMAP) in organic synthesis has
been reviewed as an efficient catalyst.4
theless, these protocols reported by others are quite useful, still
there is further scope to develop a new methodology using a less
expensive catalyst under mild reaction conditions and applicable
to a wide range of substrates in great demand.
In this Letter, we report 4-(dimethylamino)pyridine (DMAP)
catalyzed synthesis of pyran annulated heterocyles, which are ob-
tained through one-pot three-component condensation reaction of
aldehydes, ethyl cyanoacetate or malononitrile, and 4-hydroxy-
coumarin as well as condensation of aldehydes, malononitrile,
and cyclic 1,3-diketones (Scheme 1).
For this study, a mixture of 4-chlorobenzaldehyde (1 mmol) and
ethyl cyanoacetate (1 mmol) in ethanol was treated with DMAP
(0.1 mmol) at room temperature. After consumption of starting
aldehyde as checked by TLC, 4-hydroxycoumarin was added to
the reaction mixture and kept for stirring under reflux conditions.
After the completion of the reaction monitored by TLC, the reaction
mixture was brought to room temperature and the solid precipi-
tate was filtered off. The desired product 4a was obtained in 61%
yield, which was characterized by 1H NMR, 13C NMR, and by ele-
mental analysis.
The reaction was optimized using different catalysts for obtain-
ing the best yield of 4a are summarized in Table 1. It was noted
that 20 mol % of the DMAP in ethanol provides the best result in
terms of yield and time. Under solvent-free conditions, the product
was obtained in a moderate yield (56%).
Pyran annulated coumarins are widely distributed in nature5a
and exhibit diverse physiological activities.5b Compounds having
dihydropyran structural motif exhibit a wide range of biological
activities, such as diuretic, analgesic, myorelaxant activity,6 anti-
coagulant,7 anticancer,8 anti-tumoral,9 and anti-HIV.10 In addition,
they are also useful for the treatment of neurodegenerative disor-
ders including Alzheimer’s disease, amyotrophic lateral sclerosis,
Huntington’s disease, and Parkinson’s disease.11 Moreover, they
are also used as cosmetics, pigments,12 and useful as photoactive
materials.13 A considerable effort has been made for the synthesis
of pyran annulated heterocyclic derivatives due to their wide
applications. Recently, a few methods have been reported by
employing three-component reaction using DBU,14a TBAB,14b
diammonium hydrogen phosphate,14c heteropoly acids.14d Never-
After the optimization of the reaction conditions, the reaction
of benzaldehyde with ethyl cyanoacetate and 4-hydroxycoumarin
was carried out under the same reaction conditions and it affor-
ded the product 4b in 76% yield. The reaction of various other
aromatic aldehydes having substituents such as Me, NO2, OH,
⇑
Corresponding author. Tel.: +91 361 2582305; fax: +91 361 2582349.
E-mail address: atk@iitg.ernet.in (A.T. Khan).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.019

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A. T. Khan et al. / Tetrahedron Letters 52 (2011) 5327–5332
Cl, and Br were examined with ethyl cyanoacetate and 4-
OH
O
NH2
hydroxycoumarin using identical reaction conditions and resulted
in products 4c–i (Table 2, entries 3–9) in good yields. Similarly,
the reaction of aromatic aldehydes with malononitrile and 4-
hydroxycoumarin was also carried out using same mol % of DMAP
under identical reaction conditions and the products 4j–k were
obtained in excellent yields.
The present protocol was extended using dimedone and the
reaction of benzaldehyde, ethyl cyanoacetate, and dimedone was
carried out under similar reaction conditions. The desired product
4l was obtained in 94% yield. The reaction of other aromatic alde-
hydes substituted with Cl, Me, NO2, and MeO was also performed
with dimedone and ethyl cyanoacetate, the desired products
4m–p were isolated in good yields (Table 3, entries 2–5). The reac-
tion of 4-chloroaldehyde with malononitrile and dimedone was
performed and the product 4q was obtained in good yield.
The scope of presented protocol further investigated with other
C–H activated acidic compounds such as 1,3-cyclopentadione and
1,3-cyclohexadione using 4-chlorobenzaldehyde and malononitrile
under similar reaction condition and the results were summarized
in Table 3 (entries 7–9). The reaction of 4-chloroaldehyde with
R
O
O
Ar
O
O
O
O
NH2
R
O
Ar
R
O
DMAP
EtOH, reflux
ArCHO +
NH2
CN
O
O
R
O
R=CN, COOEt
n
Ar
n= 0, 1
OH
n
O
NH2
R
O
malononitrile and
a-naphthol was performed and the product 4u
Ar
was obtained in good yield. From the above observation, it is
important to mention that the reaction was fast and also provided
better yields using either aldehyde having electron withdrawing
group viz. NO2 or with malononitrile. All the products were charac-
Scheme 1. Synthesis of pyran annulated heterocycles.
Table 1
Optimization of reaction conditions
NH2
O
CHO
OH
O
O
O
OEt
O
DMAP
NC
OEt
reflux, EtOH
O
O
Cl
Cl
1
2
3
4a
Entry
Catalyst
Solvent
Catalytic
amount (mol %)
Time
(h)
Yielda (%)
1
2
3
4
5
6
7
DMAP
Piperidine
DMAP
DMAP
DMAP
DMAP
DMAP
Neat
20
20
10
20
30
20
20
3
4
5
3
3
3
4
56
40
61
78
76
69
62
EtOH
EtOH
EtOH
EtOH
MeOH
Water
a
Isolated yield.
Table 2
Synthesis of dihydropyrano[3,2-c]chromene derivatives using aromatic aldehydes, ethyl cyanoacetate or malononitrile, and 4-hydroxycoumarin catalyzed by DMAP15
Entry
Aromatic aldehydes
Cl CHO
Product
Time (h/[min])
Yielda (%)
Mp °C (lit.)
194–195
NH2
O
[192–194]14a
O
O
OEt
OEt
1
2.5
78
O
Cl
4a
NH2
O
CHO
O
O
2
3.5
76
187–189
O
4b

A. T. Khan et al. / Tetrahedron Letters 52 (2011) 5327–5332
5329
Table 2 (continued)
Entry
Aromatic aldehydes
Product
Time (h/[min])
Yielda (%)
Mp °C (lit.)
NH2
O
O
Me
CHO
O
O
OEt
OEt
3
4.0
76
114–117
241–244
O
Me
4c
NH2
[241–243]14a
O2N
CHO
O
O
4
1.5
82
O
NO2
4d
242–245
O2N
HO
NH2
O
O
[247–250]14c
O
OEt
OEt
CHO
5
6
3.5
3.0
80
67
NO2
O
O
O
4e
NH2
CHO
OH
208–210
O
O
4f
Cl
NH2
O
O
O
OEt
CHO
7
5.0
64
209–212
O
Cl
O
4g
NH2
Br
O
O
OEt
OEt
CHO
Br
8
4.5
4.0
[5]
81
80
94
92
196–198
O
4h
NH2
O
Br
CHO
O
O
9
142–144
O
Br
Cl
4i
NH2
264–266
[263–265]14d
Cl
CHO
CHO
CN
CN
O
O
10
O
4j
NH2
258–260
[253–255]14a
Me
O
O
11
[10]
O
Me
4k
a
Isolated yield.

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A. T. Khan et al. / Tetrahedron Letters 52 (2011) 5327–5332
Table 3
Synthesis of chromene derivatives using diketones, ethyl cyanoacetate or malononitrile, and aromatic aldehydes catalyzed by DMAP15
Entry
1,3-Diketones
Product
Time (h/[min])
Yielda (%)
Mp °C (lit.)
O
NH2
O
O
O
OEt
OEt
1
3.5
94
144–146
O
O
4l
O
NH2
O
O
O
2
5.0
92
139–142
O
O
Cl
4m
NH2
O
O
O
OEt
OEt
3
4.5
91
151–152
O
O
4n
NH2
Me
O
O
4
1.5
91
154–156
O
NO2
OEt
4o
NH2
O
O
O
O
5
3.5
91
131–134
O
O
OMe
4p
NH2
213–215
O
[212–214]14e
CN
6
[15]
94
O
O
4q
Cl
O
O
NH2
CN
O
7
8
9
[10]
[10]
2.5
98
95
95
216–218
241–243
163–165
Cl
O
4r
O
O
NH2
CN
O
O
O
O
O
Cl
4s
NH2
O
OEt
O
Cl
4t

A. T. Khan et al. / Tetrahedron Letters 52 (2011) 5327–5332
5331
Table 3 (continued)
Entry
1,3-Diketones
Product
Time (h/[min])
Yielda (%)
Mp °C (lit.)
OH
NH2
CN
O
10
[20]
92
244–243
Cl
4u
a
Isolated yields.
OH
Me
N
Me
95
94
93
92
91
90
89
N
O
3
ArCHO
2
Me
N Me
% Yield
O
NC
Ar
R
N
H
NC
R
Me
N
Me
+
H
H
N
O
A
B
N
O
Run 1 Run 2
Run 3 Run 4 Run 5
R
NC
R
Figure 2. Reusability of the catalyst.
1
Ar
N
H
O
Me
N
Me
N
N
Me
Me
product A was formed by the reaction of aldehyde and alkyl nitrile
in the presence of DMAP, which reacts with in situ generated carb-
anion from activated C–H acidic compounds to give intermediate
C. The intermediate C was cyclized to D in the presence of DMAP.
Finally, D tautomerized to give the desired product 4 as shown in
Scheme 2.
C
NH
NH2
R
H
Ar
R
O
O
Ar
Moreover, the structure of compound 4l was further confirmed
by X-ray crystallographic analysis (Fig. 1).16
O
O
4
D
Further the role of catalyst was ascertained by the reaction of A,
which is obtained from the reaction of 4-chlorobenzaldehyde and
malononitrile in the presence of DMAP, with 4-hydroxycoumarin
in the presence of DMAP and without DMAP. The product 4j was
obtained with DMAP within 5 min in 94% yield, whereas the same
reaction without catalyst gave only 63% yield after 1 h of stirring
under reflux conditions.
Scheme 2. Plausible mechanism for the formation of pyran annulated heterocyclic
compounds.
The reusability test was performed as follows: A mixture of 4-
chlorobenzaldehyde (2 mmol), malononitrile (2 mmol), 4-
hydroxycoumarin, and DMAP (0.4 mmol) was stirred in ethanol
(8 mL) under reflux condition. After completion of the reaction,
the solid precipitate was filtered using a Buchner funnel. The pre-
cipitate was washed with ethanol (0.5 mL). The filtrate containing
catalyst was reused for similar scale of reaction for the same sub-
strates. The procedure was repeated five times which is depicted in
Figure 2.
In summary, we have devised a simple and efficient protocol for
the synthesis of pyran annulated heterocycles using DMAP as cat-
alyst via one-pot three-component condensation reaction of an
aldehyde, ethyl cyanoacetate or malononitrile, and either 4-
hydroxycoumarin or 1,3-cyclic ketones or 2-naphthol in excellent
yields. The advantages offered by this DMAP versus known cata-
lysts are (i) inexpensive, (ii) reusable, and (iii) no need chromato-
graphic separation. The significant features of this protocol are
good yields and applicable to the broad range of substrates espe-
cially the less reactive alkyl nitrile such as ethyl cyanoacetate also
provides the desired pyran annulated heterocycles, which are not
much studied earlier.
Figure 1. ORTEP diagram of 4l (CCDC 828132).
terized by IR, 1H NMR, and 13C NMR spectra and by elemental
analysis.
The formation of various pyran annulated heterocyclic com-
pounds can be rationalized as follows. Initially, the Knovengel

5332
A. T. Khan et al. / Tetrahedron Letters 52 (2011) 5327–5332
Chem. 1992, 35, 2735; (b) Patil, A. D.; Freyer, A. J.; Eggleston, D. S.;
Acknowledgments
Waltiwanger, R. C.; Bean, M. F.; Taylor, P. B.; Caranfa, M. J.; Breen, A. L.;
Bartus, H. R.; Johnson, R. K.; Hertzberg, R. P.; Westley, J. W. J. Med. Chem. 1993,
36, 4131.
M.L. is thankful to CSIR, New Delhi for his research fellowship.
S.A. and M.M.K acknowledge UGC, New Delhi for their research
fellowships. The authors are grateful to the Department of Science
and Technology for providing single XRD facility under FIST pro-
gram as well as to the Director, IIT Guwahati for providing general
facility. We are also grateful to the referees for their valuable
comments and constructive suggestions.
11. (a) Foye, W. O. Principi di Chemico Farmaceutica; Piccin: Padora, Italy, 1991. P
416.; (b) Andreani, L. L.; Lapi, E. Bull. Chim. Farm. 1960, 99, 583; (c) Zhang, Y. L.;
Chen, B. Z.; Zheng, K. Q.; Xu, M. L.; Lei, X. H.; Yaoxue, X. B. Chem. Abstr. 1982, 17,
17. Chem. Abstr. 1982, 96, 135383e; (d) Bonsignore, L.; Loy, G.; Secci, D.;
zCalignano, A. Eur. J. Med. Chem. 1993, 28, 517.
12. Ellis, G. P. In The Chemistry of Heterocyclic Compounds Chromenes, Chromanes
and Chromones; Weissberger, A., Taylor, E. C., Eds.; John Wiley: New York, NY,
1977; p 11. Chapter II.
13. Arnesto, D.; Horspool, W. M.; Martin, N.; Ramos, A.; Seaone, C. J. Org. Chem.
1989, 54, 3069.
Supplementary data
14. (a) Khurana, J. M.; Nand, B.; Saluja, P. Tetrahedron 2010, 66, 5637; (b) Khurana,
J. M.; Kumar, S. Tetrahedron Lett. 2009, 50, 4125; (c) Heravi, M. M.; Sadjadi, S.;
Haj, N. M.; Oskooie, H. A.; Bamoharram, F. F. Catal. Commun. 2009, 10, 1643.
and references therein; (d) Abdolmohammadi, S.; Balalaie, S. Tetrahedron Lett.
2007, 48, 3299.
Supplementary data (X-ray crystallographic data (CIF files) of 4a
and 4l and spectral data of all compounds and copies of 1H and 13
C
NMR spectra of products) associated with this article can be found,
in the online version, at doi:10.1016/j.tetlet.2011.08.019.
15. General procedure for the synthesis of pyran annulated heterocyclic compounds:
Into a mixture of an aromatic aldehyde (1 mmol) and ethyl cyanoacetate or
malononitrile (1 mmol) in 4 mL of ethanol was added the catalyst DMAP
(0.025 g, 0.2 mmol) and kept for stirring at room temperature. The solid
precipitate was formed immediately in case of malononitrile or it took 20–
30 min. for ethyl cyanoacetate. Then C–H activated acidic compound (1 mmol)
was added into the reaction mixture and it was kept for stirring under reflux
conditions. After sometime, the reaction mixture was converted into clear
solution. After the completion of the reaction, the solid precipitate came out
under hot conditions at the stipulated time mentioned in the Table 2 and Table
3. The reaction mixture was brought to room temperature and the solid
precipitate was filtered off to obtain the desired product. Ethyl 2-amino-4-(3-
hydroxyphenyl)-5-oxo-4,5-dihydropyrano[3,2-c]chromene-3-carboxylate Ethyl 2-
amino-7,7-dimethyl-5-oxo-4-phenyl-5,6,7,8-tetrahydro-4H-chromene-3-carboxylate
References and notes
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(4l): Yield 0.320 g, 94%. Solid, mp 144–146 °C. IR
mmax (KBr): 3403, 3290, 2956,
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.
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