Potassium exchanged layered zirconium phosphate as catalyst in the preparation of 4H-chromenes

Article abstract of DOI:10.1016/j.tetlet.2005.03.075

Substituted 4H-chromenes were easily prepared by reaction of salicylaldehydes and ethylcyanoacetate in solvent free conditions using potassium exchanged layered zirconium phosphate as catalyst.

Full text of DOI:10.1016/j.tetlet.2005.03.075

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3497–3499
Potassium exchanged layered zirconium phosphate as catalyst
in the preparation of 4H-chromenes
Massimo Curini,a,* Francesco Epifano,a Stefano Chimichi,b Francesca Montanari,a
Morena Nocchettic and Ornelio Rosatia,*
aDipartimento di Chimica e Tecnologia del Farmaco, Sezione Chimica Organica, Via del Liceo, 06123 Perugia, Italy
bDipartimento di Chimica Organica ‘Ugo Schiff ’, Via della Lastruccia 13, 50019 Sesto F. no, Italy
cDipartimento di Chimica, Sezione Chimica Inorganica, Via del Liceo, 06123 Perugia, Italy
Received 16 February 2005; revised 11 March 2005; accepted 15 March 2005
Available online 8 April 2005
Abstract—Substituted 4H-chromenes were easily prepared by reaction of salicylaldehydes and ethylcyanoacetate in solvent free
conditions using potassium exchanged layered zirconium phosphate as catalyst.
ꢀ 2005 Elsevier Ltd. All rights reserved.
In recent years, there has been an increasing emphasis in
the use of acidic and basic solids in liquid organic syn-
thesis.1 Many examples exist which demonstrate achiev-
ing better yields, higher selectivity and shorter reaction
times as a result of a reaction carried out with heteroge-
neous catalysts under milder reaction conditions than
those employed in conventional synthetic methods. In
previous years we reported that layered potassium
exchanged zirconium phosphate [Zr(KPO4)2] is an
excellent heterogeneous catalyst for Michael addition,
Henry and Knoevenagel reactions, respectively.2 In
continuing our research into the development of new
methods for the formation of carbon–carbon bonds
using heterogeneous catalysts, we decided to investigate
the use of Zr(KPO4)2 in the reaction of salicylaldehydes
with cyanoacetates for the preparation of 4H-chrom-
enes. Our interest for this class of compound derived
from biological consideration: recently Huang and co-
workers3 reported that 4H-chromene derivatives bind
Bcl-2protein and induce apoptosis in tumour cells. To
our knowledge, 4H-chromenes were prepared from sali-
The reaction was carried out by addition of salicylalde-
hyde (1 mmol) to a well stirred mixture of ethylcyano-
acetate (2mmol) and Zr(KPO 4)2 (50 mg/mmol alde-
hyde) at 40 ꢁC (Scheme 1).7 The reaction takes from
0.5 h to 10 h and after a simple work-up affords a good
yield of 4H-chromenes (Table 1). The reaction product
consists of a mixture of two diastereoisomers with differ-
ent molar ratios. It is important to note that during the
purification of 4H-chromenes by crystallization, sponta-
neously conversion produces the more abundant diaste-
reoisomer. The existence of an equilibrium between the
two diastereoisomeric forms has been confirmed by leav-
ing the crystallized product in CDCl3 solution and ana-
1
lyzing its rate of conversion by H NMR analysis. For
the reaction of salicylaldehyde with ethylcyanoacetate
(entry 1b), it was found that the structure of the preva-
lent diastereoisomer can be attributed to an erythro con-
figuration by comparison with the data reported in the
literature.5,8
This methodology is also applicable to the 2-hydroxy-1-
naphthaldehyde which affords more complex 4H-chro-
mene models (Scheme 2) in good yield (R = methyl:
15 h, 72%;6 R = ethyl: 3 h, 67%).
cylaldehydes and cyanoacetates in heterogeneous liquid
4,5
phase catalysis using only Al2O3
sieves.6
and molecular
The efficiency of Zr(KPO4)2 in the synthesis of 4H-chro-
mene is more favourable than alternative reagents
reported in the literature. For example entries 1a, 5a
and 7b provided in our case 95%, 72% and 94% yield,
respectively, instead of the reported 75%,6 66%6 and
86% yield,3 respectively. This method offers several
Keywords: 4H-Chromene; Potassium exchanged layered zirconium
phosphate; Bcl-2protein; Cyclization; Salicylaldehydes.
*
Corresponding authors. Tel.: +39 075 585 5106; fax: +39 075 585
5116 (M.C.); tel.: +39 075 585 5103; fax: +39 075 585 5116 (O.R.);
e-mail addresses: curmax@unipg.it; ornros@unipg.it
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.075

3498
M. Curini et al. / Tetrahedron Letters 46 (2005) 3497–3499
H
H
CO2R1
CO2R1
NC
CO2R1
NC
2'
1'
5
8
CO2R1
4
CHO
OH
3
2
R 6
H
+
Zr(KPO4)2 (50mg/mmol aldehyde),
CNCH2CO2R1 (2.0 equiv),neat,40°C
R
H
O
R
7
O
NH2
NH2
1
Threo
Erythro
Scheme 1.
Table 1. Synthesis of 4H-chromenes with different alkyl cyanoacetates using Zr(KPO4)2 as catalyst in solvent free condition
Entry
Salicylaldehydes
Cyanoacetate
(b) R1 = ethyl– (c) R1 = butyl–
Time (h) Yield (%) Time (h) Yield (%)
(a) R1 = methyl–
Time (h) Yield (%)
(d) R1 = allyl–
Time (h)
Yield (%)
a
1
5-2Methyl–
—
1
95
2
88
1
84
3
88
297
5-Bromo-3-methoxy–
5-Nitro–
294
296
10
93
3
4
5
6
7
8
1
924
1
78
85
83
3
91
98
10
293
91
279
1
1
287
3-Methoxy–
4-Methoxy–
5-Bromo–
725
95
288
4
9
4
71
6
1
89
81
10
85
1
723
98
97
3
91
10
90
286
5-Chloro–
1
94
a The diastereoisomer more abundant has an erythro configuration.
References and notes
CN
CO2R
CO2R
Zr(KPO4)2,
CHO
OH
1. Hattori, H. Chem. Rev. 1995, 195, 534–558; Corma, A.
Chem. Rev. 1995, 195, 559–614.
CNCH2CO2R
2. Curini, M.; Rosati, O.; Costantino, U. Curr. Org. Chem.
2004, 8, 591–606.
O
NH2
3. Niefang, Y.; Aramini, J. M.; Germann, M. W.; Huang, Z.
Tetrahedron Lett. 2000, 41, 6993–6996.
9a R = Me
9b R = Et
4. Fujimoto, A.; Sakurai, A. Synthesis 1977, 871–872.
5. Shi, D. Q.; Wang, X. S.; Tu, S. J.; Yao, C. S.; Wang, Y. C.
Jiegou Huaxue 2002, 21(1), 60–63.
Scheme 2.
6. Roudier, J. F.; Foucaud, A. Synthesis 1984, 159–
160.
advantages; such as a high rate of conversion, good
reaction times and cleaner reaction profiles. It requires
simple experimental and work-up procedures, which
may be carried out in the absence of solvents and
provide high regioselectivity. The preparation of
Zr(KPO4)2, does not require any specific skills9 and
may also be recycled.10
7. General reaction procedure: a mixture of cyanoacetate
(2mmol) and Zr(KPO 4)2 (50 mg) was stirred at 60 ꢁC
under nitrogen. After 30 min, salicylaldehyde (1 mmol),
was added and the reaction mixture stirred for the
appropriate time (see Table 1). The mixture was diluted
with dichloromethane (5 ml) and the catalyst removed by
filtration. The filtrate was concentrated under vacuum and
purified by crystallization. All compounds were charac-
1
terized by H, 13C NMR and GC–MS. Selected spectral
In summary, we describe an efficient procedure for the
synthesis of substituted 4H-chromenes from several
salicylaldehydes and cyanoacetic esters. Potassium
exchanged layered zirconium phosphate is used as the
catalyst and the reaction takes place in solvent free
conditions. This method could be employed in the
preparation of a wide variety of 4H-chromene models
under extremely mild conditions.
data.
Methyl 2-amino-4-(1-cyano-2-methoxy-2-oxoethyl)-6- nitro-
4H-chromene-3-carboxylate (entry 4a): pale yellow solid
(ethanol), mp 156 ꢁC. 1H NMR (400 MHz, CDCl3)
d = 3.85 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 4.08 (d,
J = 3.5 Hz, 1H, H-3), 4.82(d, J = 3.5 Hz, 1H, CHCN),
6.24 (br s, 2H, NH2), 7.26 (d, J = 9.0 Hz, 1H, H-8), 8.09
(d, J = 2.4 Hz, 1H, H-5), 8.25 (dd, J = 2.4, 9.0 Hz, 1H, H-
7). 13C NMR (100, 12MHz, CDCl 3) d = 37.1, 46.9, 52.1,
54.2, 73.1, 115.2, 118.1, 121.6, 124.7, 125.6, 144.7, 155.1,
161.9, 165.5, 168.3. GC–MS m/z: 305, 249, 233, 216, 200,
189, 186, 170, 158, 142, 114. 88.
Acknowledgments
Ethyl 3-amino-1-(1-cyano-2-ethoxy-2-oxoethyl)-1H-benzo[f]-
chromene-2-carboxylate (9b): yellow solid (ethanol), mp
118 ꢁC. 1H NMR (400 MHz, CDCl3) d = 1.35 (t,
J = 7.1 Hz, 3H, CH3), 1.38 (t, J = 7.1 Hz, 3H, CH3), 3.84
(d, J = 2.3 Hz, 1H, H-1), 4.08–4.43 (m, 4H, 2 · OCH2),
5.42(d, J = 2.3 Hz, 1H, CHCN), 6.54 (br s, 2H, NH2),
Financial support from MIUR, National Project ÔSvi-
luppo di processi ecocompatibili nella sintesi organicaÕ
and CEMIN (Centro di Eccellenza Materiali Innovativi
Nanostrutturati per applicazioni chimiche, fisiche e bio-
mediche) is gratefully acknowledged.

M. Curini et al. / Tetrahedron Letters 46 (2005) 3497–3499
3499
7.26 (d, J = 9 Hz, 1H, H-5), 7.54 (t, J = 7.5 Hz, 1H,
H-8), 7.70 (t, J = 7.5 Hz, 1H, H-9), 7.84 (d, J = 9 Hz, 1H,
H-6), 7.92(d, J = 8 Hz, 1H, H-7), 8.19 (d, J = 8 Hz). 13C
NMR (100, 12MHz, CDCl 3) d = 14.2, 14.8, 34.5, 46.9,
60.3, 62.9, 73.5, 115.0, 115.7, 117.1, 122.1, 125.6, 128.2,
129.5, 130.0, 130.3, 131.6, 148.7, 162.8, 165.4, 168.6.
GC–MS m/z: 281, 250, 223, 207, 193, 164, 138, 126, 114,
96, 82.
8. Kokila, M. K.; Nirmala, K. A.; Puttaraja; Kulkarni, M.
V.; Shivaprakash, N. C. Acta Crystallogr. C 1992, C48(9),
1619–1622.
9. Costantino, U.; Curini, M.; Marmottini, F.; Rosati, O.;
Pisani, E. Chem. Lett. 1994, 2215–2218.
10. The catalyst was washed with dichloromethane/methanol
and dried at 180 ꢁC for 2h. The Zr(KPO 4)2 was then
reused for four cycles without consistent loss of activity.