DBU: A highly efficient catalyst for one-pot synthesis of substituted 3, 4- dihydropyrano[3, 2-c]chromenes, dihydropyrano[4, 3-b]pyranes, 2-amino-4H- benzo[h]chromenes and 2-amino-4H benzo[g]chromenes in aqueous medium

Article abstract of DOI:10.1016/j.tet.2010.05.082

We have reported DBU catalyzed one-pot synthesis of 3, 4-dihydropyrano[3, 2-c]chromenes, dihy- dropyrano[4, 3-b]pyranes, 2-amino-4H-benzo[h]chromenes and 2-amino-4H-benzo[g]chromenes from aldehydes, active methylene compounds malononitrile/ethyl cyanocace

Full text of DOI:10.1016/j.tet.2010.05.082

Tetrahedron 66 (2010) 5637e5641
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
DBU: a highly efficient catalyst for one-pot synthesis of substituted 3,4-
dihydropyrano[3,2-c]chromenes, dihydropyrano[4,3-b]pyranes, 2-amino-4H-
benzo[h]chromenes and 2-amino-4H benzo[g]chromenes in aqueous medium
*
Jitender M. Khurana , Bhaskara Nand, Pooja Saluja
Department of Chemistry, University of Delhi, Delhi 110007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
We have reported DBU catalyzed one-pot synthesis of 3,4-dihydropyrano[3,2-c]chromenes, dihy-
dropyrano[4,3-b]pyranes, 2-amino-4H-benzo[h]chromenes and 2-amino-4H-benzo[g]chromenes from
aldehydes, active methylene compounds malononitrile/ethyl cyanocacetate, and 4-hydroxycoumarin/
4-hydroxy-6-methylpyrone/1-naphthol/2-hydroxynaphthalene-1,4-dione in water under reflux. The
attractive features of this process are mild reaction conditions, reusability of the reaction media, short
reaction times, easy isolation of products, and excellent yields.
Received 27 April 2010
Received in revised form
19 May 2010
Accepted 21 May 2010
Available online 26 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU)
Chromenes
Synthesis in water
Multi-component reaction
Aldehydes
1. Introduction
widely employed as cosmetics, pigments,10 and potential bio-
degradable agrochemicals11 and exhibits a wide spectrum of bio-
The development of multi-component reactions (MCRs) designed
to produce elaborate biologically active compounds has become an
important area of research in organic, combinatorial, and medicinal
chemistry.1 One-pot multi-component reaction strategies offer sig-
nificant advantages overconventional linear-type syntheses by virtue
of their convergence, productivity, facile execution and high yields.2
Developing MCR protocols in water or aqueous medium is an active
area of research in this direction. It constitutes an attractive synthetic
strategy in drug discovery research, since they provide easyand rapid
access to large libraries of organic compounds with diverse sub-
stitution patterns.3 The network of hydrogen bonds in water
influences the reactivity of the substrates, which makes it an ideal
solvent.4 It isalsoproposedthatthereactionswith negative activation
volume might be facilitated by water.5 MCRs are believed to exhibit
negative activation volumes owing to the condensation of several
molecules into a single reactive intermediate and product.6
logical activities.12 Benzo[g]chromenes also show a variety of
biological activities, including anticancer,13 anti-inflammatory,14
antimalarial,15 and pesticides activities.16 This moiety also occurs
in different natural products.17
A number of methods have been reported for the syntheses of
2-amino-4H-benzo[h]chromenes.18 However, comparatively fewer
methods have been described for the synthesis of dihydropyrano
[3,2-c]chromenes19 and 2-amino-4H-benzo[g] chromenes.20 Some
of these procedures require the use of toxic organic solvents,
expensive catalysts and tedious workup. Thus, in view of the
importance of chromenes for diverse therapeutic activity and in
continuation to our endeavor of developing methodologies aimed
at synthesis of polyfunctionalized heterocyclic moieties,21 we
considered it necessary to develop a general rapid, high yielding,
environmentally benign and easy synthetic protocol for a variety
of chromene derivatives.
Dihydropyrano[3,2-c]chromenes and their derivatives are of
considerable interest as they possess a wide range of biological
properties,7,8 such as spasmolytic, diuretic, anti-coagulant, anti-
cancer, and anti-anaphylactic activity.9 Benzo[h]chromenes are
2. Results and discussion
We report in this paper, highly efficient one-pot synthesis of
a variety of chromene derivatives namely substituted 3,4-dihy-
dropyrano[3,2-c]chromenes (2aep), dihydropyrano[4,3-b]pyranes
(2qes), 2-amino-4H-benzo[h]chromenes (3ael) and 2-amino-4
* Corresponding author. Tel.: þ91 11 27667725 1384; fax: þ91 11 27666605;
e-mail address: jmkhurana@chemistry.du.ac.in (J.M. Khurana).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.05.082

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J.M. Khurana et al. / Tetrahedron 66 (2010) 5637e5641
H-benzo[g]chromenes (4ael) catalyzed by 1,8-diazabicyclo[5.4.0]
undec-7-ene (DBU) in water under reflux. Reactions were complete
in 5e180 min and high yields of the products were obtained by
a simple workup. Careful literature analysis revealed that a variety
of bases with pKa ranges from 4 to 11 have been used for some
multi-component reactions. We speculated that use of neutral
organic bases that have high basicity, and can form a stable pro-
tonated species, may suppress the formation of enaminonitrile and
other side products. 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU)
fulfills these requirements, and has been used in many organic
transformations in recent years.22 It is a sterically hindered amidine
base and especially useful where side reactions due to the inherent
nucleophilicity of a basic nitrogen are a problem.23 DBU is one of
the strongest organic neutral base (pKa¼12) and the þM effect of
the adjacent nitrogen stabilizes the protonated species.
v) at room temperature using 10 mol % of DBU. The yield was how-
ever inferior (76%) and the reaction was not completed even after
30 min. Thus refluxing all the components in presence of 10 mol % of
DBU in water proved to be the optimum conditions for this reaction.
Therefore reactions of diversely substituted aromatic, hetero-
aromatic, and aliphatic aldehydes were attempted with malono-
nitrile and 4-hydroxycoumarin in water under reflux in the
presence of 10 mol % of DBU. All the reactions yielded corre-
sponding dihydropyrano[3,2-c]chromenes (Table 1, entries 2aen)
in excellent yields. All the utilized functionalities were found to be
compatible under the reaction conditions. In order to broaden the
scope of the present method, the replacement of malononitrile
with ethyl cyanoacetate was examined. To our delight, the reaction
underwent successful condensation under similar reaction condi-
tions, to afford the corresponding chromene derivatives in high
yields (Table 1, entries 2oep). Reactions were also attempted by
replacing 4-hydroxycoumarin with 4-hydroxy-6-methylpyrone
(1b). The components underwent successful condensation to give
dihydropyrano[4,3-b]pyranes (Table 1, entries 2qes) in nearly
quantitative yields (Scheme 1).
Inspired with the catalytic potential of DBU, we examined first the
catalytic role of DBU in the synthesis of 3,4-dihydropyrano[3,2-c]
chromenes via three-component condensation of aldehydes, malo-
nonitrile or ethyl cyanoacetate and
a-hydroxy CeH acid, i.e., 4-
hydroxycoumarin (1a). The reaction of 4-chlorobenzaldehyde
(1 mmol), malononitrile (1.5 mmol), and 4-hydroxycoumarin
(1 mmol) was carried out in the presence of varying amounts of DBU
underreflux. Itwasobservedthattheuseof10 mol %DBUasacatalyst
in aqueous mediumyielded the desired product, to afford 2-amino-4-
(4-chlorophenyl)-5-oxo-4H,5H-pyrano[3,2-c]chromene-3-carbon-
itrile, in 93% yield in 5 min (Scheme 1, Table 1, entry 2a). When this
reaction was repeated at room temperature, no desired product
formation was observed. However, the product formation was also
observed when the reactionwas carried out inwater/ethanol (1:1, v/
Encouraged bytheseresults,weattempted thepresentprotocol for
condensation of aldehydes, malononitrile, and 1-naphthol. Duringour
exploratory experiments, we observed that 4-chlorobenzaldehyde
underwent the three-component condensation smoothly in the
presence of 10 mol % of DBU under reflux to afford 95% of 2-amino-4-
(4-chlorophenyl)-4H-benzo[h]chromene-3-carbnitrile
in
5 min
(Table 2, entry 3a). Thereafter, a series of differently substituted 2-
amino-4-aryl-4H-benzo[h]chromene derivatives were prepared from
different aromatic aldehydes bearing electron-withdrawing and
electron-donating groups using 10 mol % of DBU in aqueous medium
under reflux in high yields (Scheme 2, Table 2, entries 3aek).
It was observed that with ethyl cyanoacetate a slightly longer
reaction time was needed to give reasonably high yields (Table 2,
entry 3l). These results clearly indicate that reactions can tolerate
a wide range of differently substituted aromatic aldehydes. How-
ever aliphatic aldehydes did not undergo condensation even using
higher amount of the catalyst.
Further to realize the generality and versatility of the catalyst,
this novel protocol was extended for the synthesis of 2-amino-4H-
benzo[g]chromenes (4ael) by one-pot condensation of aromatic
aldehydes (1 mmol), malononitrile or ethyl cyanoacetate
(1.5 mmol), and 2-hydroxynaphthalene-1,4-dione (1 mmol) in
aqueous media under reflux in the presence of 10 mol % of DBU
(Scheme 3).
Scheme 1.
Table 1
DBU catalyzed three-component synthesis of substituted dihydropyrano[3,2-c]chromene and dihydropyrano[4,3-b]pyranes (Scheme 1)
Product
R
R1
Time (min)
Activated CeH acid
Yield (%)
Mp (ꢀC) (obsd)
Mp (ꢀC) (lit.)19
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
2s
4-ClC6H4
C6H5
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
COOC2H5
COOC2H5
CN
5
7
5
8
10
5
12
5
8
12
12
12
15
15
20
15
12
15
10
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
94
92
94
88
86
91
84
89
88
86
85
87
83
81
89
91
88
86
90
260e262
256e258
252e254
253e255
248e250
256e258
266e267
262e263
242e243
258e259
224e225
250e252
250e252
243e245
192e194
241e243
221e223
200e201
210e212
263e265
258e260
254e256
254e255
247e249
258e260
265e266
259e261
240e242
257e259
223e225
252e253
250e252
242e245
191e193
240e242
223e225
200e202
211e213
4-BrC6H4
4-CH3C6H4
4-CH3OC6H4
4-O2NC6H4
4-HOC6H4
4-FC6H4
3-ClC6H4
2,4-Cl2C6H3
4-(CH3)2N C6H4
2-Furanyl
(CH3)2 CH
CH3(CH2)2
4-ClC6H4
4-NO2C6H4
C6H5
4-CH3OC6H4
4-O2NC6H4
CN
CN

J.M. Khurana et al. / Tetrahedron 66 (2010) 5637e5641
5639
Table 2
According to the proposed mechanisms, the first step of this
reaction is the formation of Knoevenagel product by the conden-
sation of an aldehyde with malononitrile.18e20 During such base
catalyzed three-component reaction, formation of many side
products such as enaminonitrile, higher adducts, reduced products,
and malononitrile self addition products have been noticed.24 We
believe that higher basicity, and stability of DBUeHþ species gen-
erated in this reaction suppresses the formation of these side
products and hence yield of the product increases.
DBU catalyzed three-component synthesis of substituted 2-amino-4H-benzo[h]
chromenes (Scheme 2)
Product
R
R1
Time Yield Mp (ꢀC)
(min) (%) (Obsd)
Mp (ꢀC)
(lit.)18
3a
3b
3c
3d
3e
3f
3g
3h
3i
4-ClC6H4
C6H5
CN
CN
CN
CN
CN
CN
CN
CN
CN
5
6
95
94
96
88
95
86
91
86
89
80
81
82
232e234 232e233
218e219 217e219
239e241 241e243
205e206 204e206
237e238 238e239
246e248 247e249
236e237 235e237
214e215 214e216
214e216 215e216
184e186 180e189
209e210 209e211
162e164 161e163
4-BrC6H4
4-CH3C6H4
4-O2NC6H4
4-HOC6H4
4-FC6H4
2,4-Cl2C6H3
3-O2NC6H4
3,4,5-(CH3O)3C6H2 CN
5
10
5
10
5
7
8
10
10
The
formed initially by Knoevenagel condensation in the presence of
DBU undergo subsequent reactions with -hydroxy CeH acids,
a
-cyanocinnamonitrile or
a-carbethoxycinnamonitrile
a
e.g., 4-hydroxycoumarin, 4-hydroxy-6-methylpyrone, 1-naphthol
or 2-hydroxynaphthalene-1,4-dione in the presence of DBU to
give the desired products (Scheme 4). This has been confirmed by
3j
3k
3l
3,4-(CH3O)2C6H3
2-ClC6H4
CN
COOC2H5 15
independent reactions of
a-cyano-4-chlorocinnamonitrile and
a-carbethoxy-4-chlorocinnamonitrile with 4-hydroxycoumarin in
the presence of DBU, which gave the desired products in 95% and
92%, respectively. The three-component reactions in the absence
of DBU showed the formation of
a-cyanocinnamonitrile or
a-carbethoxycinnamonitriles only. The reaction media can be
reused for further reactions. For example, after completion of the
reaction, the solid product was collected by filtration (entry 2a).
To the filtrate, 4-chlorobenzaldehyde, malononitrile, and
4-hydroxycoumarin were added in the same molar ratio without
Scheme 2.
Scheme 3.
Diversely substituted aromatic aldehydes underwent this three-
component cyclo-condensation reaction with malononitrile and
2-hydroxynaphthalene-1,4-dione to produce 2-amino-4-aryl-5,10-
dioxo-5,10-dihydro-4H-benzo[g]chromene-3-carbonitriles in excel-
lentyields(Table 3, entries4aeh). Reactionofaromaticaldehydesand
2-hydroxynaphthalene-1,4-dione, with ethyl cyanoacetate in place of
malononitrile also underwent successful condensation under similar
conditions, to afford a series of ethyl-2-amino-4-aryl-5,10-dioxo-5,
10-dihydro-4H-benzo[g]chromene-3-carboxylate derivatives in high
yields (Table 3, entries 4iel). The reactions were remarkably clean,
and no chromatographic separation was required.
Table 3
DBU catalyzed three-component synthesis of substituted 2-amino-4H-benzo[g]
chromenes (Scheme 3)
Product
R
R1
Time Yield Mp (ꢀC)
(min) (%) (obsd)
Mp (ꢀC)
(lit.)20
4a
4b
4c
4d
4e
4f
4g
4h
4i
4-O2NC6H4
C6H5
CN
CN
CN
CN
CN
CN
CN
40
60
90
90
90
90
90
150
90
87
85
90
89
87
86
85
90
88
86
85
238e240 234e235
260e262 261e262
242e244 242e244
250e254 293e295
244e246 253e255
4-CH3C6H4
2,4-Cl2C6H3
4-BrC6H4
2-ClC6H4
4-FC6H4
3,4,5-(CH3O)3C6H2 CN
4-O2NC6H4
4-FC6H4
240
>300
240e242 286e288
276e278 286e288
170e172 194e196
214e216 203e205
184e186 223e224
154e156 194e196
COOC2H5 120
COOC2H5 180
COOC2H5 120
COOC2H5 120
4j
4k
4l
2-O2NC6H4
3-BrC6H4
Scheme 4.

5640
J.M. Khurana et al. / Tetrahedron 66 (2010) 5637e5641
additional load of DBU. The reaction mixture was refluxed for
specified time, marginal loss of the yield was observed in first
three runs (94%, 92%, and 85%), while in fourth and fifth run the
yield dropped to 75% and 65%, respectively.
(m, 2H, Ar), 7.83 (d, J¼7.2 Hz, 1H, Ar); 8.20 (d, J¼8.1 Hz, 1H); m/z
332.0716 [Mþ].
4.2.3. 2-Amino-4-(4-nitrophenyl)-5,10-dioxo-5,10-dihydro-4H-
benzo[g]chromene-3-carbonitrile (4a). nmax (KBr) 3458, 3354, 3190,
3. Conclusion
2925, 2199, 1664, 1594, 1516 cmꢁ1
;
dH (300 MHz, CDCl3þDMSO-d6)
7.54e8.36 (m, 8H, Ar), 6.55 (s, 2H, NH2), 4.90 (s, 1H, CH); dC
(300 MHz, CDCl3þDMSO-d6) 87.23, 181.67, 163.81,154.68, 153.61,
151.81, 139.56, 138.98, 135.93, 135.15, 133.85, 131.33, 131.29, 128.73,
126.83, 123.57, 62.09, 41.54; m/z 374 [MH]þ.
In summary, we have developed a novel synthetic methodology
for the synthesis of pyran annulated heterocyclic systems using
10 mol % DBU as a catalyst and moreover reusability of the reaction
media without significant loss of activity was an added advantage.
Acknowledgements
4. Experimental
4.1. General
B.N. thanks C.S.I.R., New Delhi, India for the grant of Junior and
Senior Research Fellowships.
All of the chemicals used were purchased from SigmaeAldrich
and used as received. All the synthesized compounds are re-
portedly known, and were identified by comparison of spectral
and physical data with the literature. Thin layer chromatography
was used to monitor reaction progress. Compounds were purified
by crystallization through hot ethanol. Melting points were de-
termined on a melting point apparatus and are uncorrected. IR
(KBr) spectra were recorded on PerkineElmer FTIR spectropho-
tometer and the values are expressed as nmax cmꢁ1 Mass spectral
data were recorded on a Waters micromass LCT Mass Spectrom-
eter and on JEOL-AccuTOF JMS-T100 mass spectrometer having
a DART source. The 1H NMR and 13C NMR spectra were recorded
on Bruker Spectrospin spectrometer and Jeol JNM ECX-400P at
300 MHz and 400 MHz, respectively using TMS as an internal
Supplementary data
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2010.05.082.
References and notes
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4.2. General procedure for the synthesis of chromene
derivatives
Aldehyde (2.5 mmol), malononitrile (or ethyl cyanoacetate)
(3.75 mmol), and 10 mL of water were placed in a 50 mL round-
bottomed flask mounted over a magnetic stirrer. DBU (10 mol %,
0.25 mmol) was added to the mixture and the contents were stir-
red. To this stirred mixture, 4-hydroxycoumarin (or 4-hydroxy-6-
methylpyrone or 1-naphthol or 2-hydroxynaphthalene-1,4-dione)
(2.5 mmol) was added. The reaction mixture was refluxed for an
appropriate time as mentioned in Table 1 or Table 2 or Table 3. The
progress of the reaction was monitored by TLC, for disappearance of
aldehyde. After completion of the reaction, the reaction mixture
was allowed to cool at room temperature and water was decanted.
3 mL of Ethanol was added to the mixture and it was stirred. The
solid was collected by filtration at pump, washed with ethanol, and
crystallized from hot ethanol to obtain pure products. The aqueous
filtrate containing DBU was used as such for investigating the
recyclability of the catalyst.
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4.2.1. Spectral data of some representative products given below:
2-amino-4-(4-chlorophenyl)-5-oxo-4H,5H-pyrano[3,2-c]chromene-
3-carbonitrile (2a). nmax (KBr) 3383, 2143, 1714, 1676, 1608, 1378,
1061, 760 cmꢁ1
; dH (300 MHz, DMSO-d6) 4.46 (s, 1H, CH), 7.27e7.36
(m, 4H, Ar), 7.44 (br s, 2H, NH2), 7.49 (br s, 2H, Ar), 7.70 (t, J¼7.5 Hz,
1H, Ar), 7.88 (d, J¼7.5 Hz,1H, Ar); dC (300 MHz, DMSO-d6) 36.4, 58.7,
104.4,113.8, 117.3, 119.3, 123.3, 129.2, 130.4, 132.6, 133.7, 143.1, 153.0,
154.4, 158.9, 160.3; m/z 350.0458 [Mþ].
4.2.2. 2-Amino-4-(4-chlorophenyl)-4H-benzo[h]chromene-3-car-
15. (a) De Andrade-Neto, V. F.; Goulart, M. O. F.; Da Silva Filho, J. F.; Da Silva, M. J.;
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bonitrile (3a). nmax (KBr) 3454, 3335, 2192, 1669, 1600, 1572, 1412,
1378, 1100 cmꢁ1
;
dH (300 MHz, CDCl3): 4.79 (br s, 2H, NH2), 4.88 (s,
1H, CH), 7.01 (d, J¼8.7 Hz, 1H, Ar), 7.17e7.32 (m, 5H, Ar), 7.52e7.63

J.M. Khurana et al. / Tetrahedron 66 (2010) 5637e5641
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