Basic alumina catalysed synthesis of substituted 2-amino-2-chromenes via three-component reaction

Article abstract of DOI:10.1016/j.tetlet.2004.01.115

Substituted 2-amino-2-chromenes were obtained in excellent yield and selectivity simply by mixing malononitrile, α-naphthol and aromatic aldehydes in water in the presence of basic alumina as heterogeneous and reusable catalyst.

Full text of DOI:10.1016/j.tetlet.2004.01.115

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2297–2299
Basic alumina catalysed synthesis of substituted
2-amino-2-chromenes via three-component reaction
Raimondo Maggi,a,* Roberto Ballini,b Giovanni Sartoria and Raffaella Sartorioa
aÔClean Synthetic Methodologies GroupÕ, Dipartimento di Chimica Organica e Industriale dell’Universitꢀa,
Parco Area delle Scienze 17A, I-43100 Parma, Italy
bDipartimento di Scienze Chimiche dell’Universitꢀa, Via S. Agostino 1, I-62032 Camerino (MC), Italy
Received 8 January 2004; revised 21January 2004; accepted 23 January 2004
Abstract—Substituted 2-amino-2-chromenes were obtained in excellent yield and selectivity simply by mixing malononitrile,
a-naphthol and aromatic aldehydes in water in the presence of basic alumina as heterogeneous and reusable catalyst.
Ó 2004 Elsevier Ltd. All rights reserved.
The use of clean solvents in combination with hetero-
geneous and reusable catalysts represents one of the
more powerful green chemical technology procedures.1
The environmental acceptability of the process is
improved if the multicomponent strategy is applied.
Indeed, it is well known that the multicomponent reac-
tions (MCR), consisting of two or more synthetic steps,
which are carried out without isolation of any interme-
diate, allow to reduce time, save money, energy and raw
materials.2
2-Amino-chromenes represent an important class of
compounds being the main components of many natural
occurring products, and are widely employed as
cosmetics, pigments5 and potential biodegradable agro-
chemicals.6 These compounds are generally prepared by
reacting malononitrile, an aldehyde and an activated
phenol in the presence of organic bases like piperidine
(frequently utilised in stoichiometric amounts)7 in an
organic solvent (i.e., acetonitrile, ethanol). More recently
a green methodology based on the use of cetyltrimethyl-
ammonium chloride in water has been reported.8 Nev-
ertheless the use of efficient catalysts easily removable
and reusable is desirable, according to the requirements
of the modern large-scale organic synthesis.9
In addition the use of green solvents like water shows
both economical and synthetic advantages: not only the
chemical processes needed to produce organic solvents
will be reduced, the atmospheric pollution by escaping
VOC will be decreased and the waste treatment will be
reduced, but also dramatic rate enhancements can be
achieved in many organic reactions, that is Claisen
rearrangement, aldol condensation, Diels–Alder cyclo-
addition.3
In continuation of our investigations on the use of het-
erogeneous catalysts for fine chemicals preparation,10 we
have studied the three-component synthesis of substi-
tuted 2-amino-chromenes using c-alumina as cheap,
heterogeneous and reusable catalyst and water as solvent.
Alumina is a particularly interesting metal oxide as it is
widely used industrially as filler, adsorbent, drying
agent, catalyst, catalyst support and reagent. c-Alumina
is the transition alumina most commonly utilised to
carry out surface organic chemistry.4 In contrast to clays
and zeolites, this material does not contain accessible
channels or cavities and shows large surface area and
highly porous exteriors available to substrates.
The model reaction was carried out simply by mixing
benzaldehyde 1, malononitrile 2, a-naphthol 4 and the
heterogeneous catalyst in water and refluxing the
resulting mixture for 2 h. The process represents a typ-
ical cascade reaction2b;11 in which the benzylidenemalo-
nonitrile 3, containing the electron-poor C–C double
bond, is fast and quantitatively produced by Knoeve-
nagel addition of malononitrile to the aromatic aldehyde
and subsequent water elimination (Scheme 1).
It is well known that the first step, if carried out in protic
solvents like water, does not require any catalyst
* Corresponding author. Tel.: +39-0521-905411; fax: +39-0521-9054-
72; e-mail: raimondo.maggi@unipr.it
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.115

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R. Maggi et al. / Tetrahedron Letters 45 (2004) 2297–2299
Table 2. Synthesis of substituted 2-amino-chromenes 5
Entry
R
5 Yield (%)
5 Selectivity (%)
Scheme 1. The two steps of the three-component reaction.
a17
b18
c7c
d8
C6H5
96
94
95
97
98
89
87
84
83
98
97
2-NO2C6H4
3-NO2C6H4
4-NO2C6H4
3-pyridyl
although it results in a net dehydration.12 On the
contrary the second step, presumably involving
the ortho C-alkylation of a-naphthol by reaction with
the electrophilic C@C double bond13 and the nucleo-
philic addition of the phenolic OH group the CN moiety14
producing the final 2-amino-2-chromene 5, requires the
intervention of the catalyst, as the uncatalysed reaction
afforded the final product in only 29% yield.
97
98
e8
99
f8
4-pyridyl
91a
89a
87a
85a
g7a
h7a
i17
4-OHC6H4
4-ClC6H4
4-OCH3C6H4
a The sole by-product is the corresponding benzylidenemalononitrile.
A screening of four different heterogeneous catalysts,
namely two metal oxides and two clays, was performed
in order to find out the best solid promoter. As reported
in Table 1, basic alumina was found to be the superior
one affording the desired product in 84% yield.
distilled off and the products purified by crystallisation
from methanol. In addition, the reaction shows high
regioselectivity affording only one of the two possible
isomers that can be formed.
However, with enolizable aldehydes the yield and
selectivity of the reaction notably decrease (i.e., 41% and
53% , respectively, with isobutyraldehyde), probably due
to the possible aldol condensation side reaction.
As it is reported, c-alumina is basic and when contacted
with water it yields a basic solution,15 we suspected that
the activation of reagents in the second step could be
promoted by the basic water solution. To this end we
carried out the same reaction in the basic water obtained
after filtration of a stirred suspension of c-alumina and
we recovered compound 5 in only 25% yield, confirming
the important role of the catalyst surface in the activa-
tion of the reagents.
In summary, we have reported a new and effective
methodology for the eco-compatible preparation of
2-amino-2-chromenes via three-component reaction.
The easy purification of products simply by crystallisa-
tion, the use of water as solvent and of c-alumina as
heterogeneous and reusable catalyst suggest good
prospect for the industrial applicability of this process;
the sole drawback being represented by the fact that
only a-naphthol can be utilised as activated phenol.
Then we faced the problem of catalyst recycling. The c-
€
alumina, recovered by Buchner filtration and washed
with methanol, has been reused four times to promote
the model reaction affording the corresponding chro-
mene in 85%, 87%, 84% and 83% yield, respectively, and
with the same excellent selectivity.
The standardised methodology was applied to a variety
of aromatic aldehydes even in the presence of other
functionalities such as nitro, ether and chlorine that
under our reaction conditions were preserved (see Table
2).16
Acknowledgements
We thank the support of the Ministero dellÕIstruzione,
dellÕUniversita e della Ricerca (MIUR), Italy, and the
University of Parma (National Project ÔProcessi puliti
ꢀ
per la Chimica FineÕ). We are also grateful to the Centro
In all cases good yield and selectivity were obtained; it is
worthy to note that the purification procedure was
extremely simple as after removal of the catalyst by fil-
tration and washing with methanol, the solvents were
ꢀ
Interfacolta Misure (CIM) for the use of NMR and
mass spectrometry instruments and to Mr Pier Antonio
Bonaldi (Lillo) for technical collaboration.
References and notes
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Yield (%)
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16. Sample procedure (Table 2, entry d): c-Alumina (0.50 g),
p-nitrobenzaldehyde (0.010 mol, 1.51 g), malononitrile
(0.010 mol, 0.66 g, 0.63 mL) and a-naphthol (0.010 mol,
1.44 g) in water (10 mL) were refluxed for 3 h; the catalyst
was removed by filtration and washed with methanol
(20 mL); the solvents were distilled off and the crude was
purified by crystallisation from methanol affording 3-
amino-2-cyano-1-(4-nitrophenyl)-1H-benzo[f]chromene 5d
(3.33 g, 97%): pale yellow solid, mp 188–189 °C; 1H NMR
(DMSO-d6, 300 MHz): 5.56 (s, 1H, H-4), 7.16 (s, 2H,
NH2), 7.37 (d, 1H, J ¼ 9:0 Hz, H-9 or H-10), 7.4–7.5 (m,
2H, H-6 and H-7), 7.47 (d, 2H, J ¼ 8:5 Hz, H-20 and H-60),
7.7–8.0 (m, 2H, H-5 and H-8), 7.98 (d, 1H, J ¼ 9:0 Hz, H-
10 or H-9), 8.15 (d, 2H, J ¼ 8:5 Hz, H-30 and H-50); IR
(KBr) 3429, 3331and 2910 cm À1; MS (C.I.) m=z 344
([M+H]þ, 41%), 221 (100).
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MS) and their mps compared with literature reported
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