Hydrotalcite catalysed [4+2] cycloaddition reactions of nitroso- and azo-alkenes

Article abstract of DOI:10.1016/j.tetlet.2009.01.045

The generation of nitroso- and azo-alkenes and their [4+2] cycloaddition reactions with furan and ethyl vinyl ether, producing dihydro-1,2-oxazines and tetrahydropyridazines, by the use of catalytic Mg:Al 3:1 hydrotalcite, is described. The absence of an

Full text of DOI:10.1016/j.tetlet.2009.01.045

Tetrahedron Letters 50 (2009) 1311–1313
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Hydrotalcite catalysed [4+2] cycloaddition reactions of nitroso- and azo-alkenes
*
Américo Lemos , João Paulo Lourenço
CIQA, Departamento de Química, Bioquímica e Farmácia, Faculdade de Ciências e Tecnologia, Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
The generation of nitroso- and azo-alkenes and their [4+2] cycloaddition reactions with furan and ethyl
vinyl ether, producing dihydro-1,2-oxazines and tetrahydropyridazines, by the use of catalytic Mg:Al 3:1
hydrotalcite, is described. The absence of an organic solvent, the catalytic quantities of Ht required
together with its regeneration and reuse, may be regarded as environmentally friendly, greener and eco-
nomically advantageous over the usual methods.
Received 28 November 2008
Revised 18 December 2008
Accepted 9 January 2009
Available online 15 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Hydrotalcite
Catalysis
Nitrosoalkene
Azoalkene
Cycloaddition
1,2-Oxazine
Pyridazine
Hydrotalcite-like (Hts) anionic clays belong to the class of dou-
Likewise, in recent years, Hts have found applications in aldol
and Knoevenagel condensations, in Michael, Wadsworth–Emmons,
nitroaldol, N-oxidation and trans-esterification reactions,4 and in
[3+2] cycloaddition reactions that are used for the synthesis of
isoxazoles5 and tetrazoles.6
3þ
ble hydroxide minerals (LDHs) with the general formula Mx2þMy
ðOHÞ2ðxþyÞAy=nnꢀ ꢁ mH2O, where M2+ and M3+ are divalent and triva-
lent metals, respectively, and Anꢀ is an intercalated anion. In the
case of magnesium and aluminium as the metals these materials
are structurally described as brucite-like (Mg(OH)2) sheets where
various Mg2+ are isomorphously substituted by trivalent Al3+. The
positive charge generated by the presence of the trivalent cation
in the layer is compensated by the intercalated anion.1 These com-
pounds are usually prepared by coprecipitation followed by an
ageing time and/or a hydrothermal treatment to improve the crys-
tallinity.2 Thermal treatments convert LDHs into mixed oxides
with high surface area and strong basic properties.
The basic properties of mixed oxides obtained by calcination of
hydrotalcites are mainly associated with the Lewis basicity of the
pairs O2ꢀ Mg2+ (in the case of Mg–Al mixed hydroxides). A con-
trolled rehydration promotes a structural rearrangement, resulting
in a Meixnerit-like compound by a reconstruction process using a
memory effect and giving rise to a change in the nature of the basic
sites.3 In this case, the basic properties are influenced by the pres-
ence of intercalated hydroxide anions.
Over the last decades, the use of electron deficient nitroso–7,8
and azo-alkenes or 1,2-diaza-1,3-butadienes,9,10 in inverse electron
demand Diels–Alder cycloaddition reactions, has successfully pro-
vided routes to a large number of new 1,2-oxazine and pyridazine
derivatives. Amongst the class of heterocyclic compounds contain-
ing nitrogen, these heterocycles have proved to be useful targets,
not only due to their biological and pharmacological properties
but especially because of their wide and versatile use as synthetic
intermediates.11,12
Base induced dehydrohalogenation of
a-halo-oximes and -
hydrazones I constitutes the general method for the generation
of nitroso- and azo-alkenes II. Their interception ‘in situ’ by a wide
range of nucleophilic olefins or heterocycles produces the cycload-
ducts III in highly regioselective fashion (Scheme 1). In order for
the reaction be efficient a low concentration of the transient nitro-
so- or azo-alkene and concomitantly a great excess of the dieno-
phile (usually a 10-fold mol equiv) are required. These conditions
are commonly attained using a substantial volume of organic sol-
vent and an inorganic base, the low solubility of which ensures a
slow rate of dehydrohalogenation.
Due to the ability of changing the nature of the basic sites by
controlled hydration procedures, these solids show a great poten-
tial to be used as catalysts for reactions that need Lewis basic sites,
Brønsted basic sites or even pairs of acid-base sites.
During our studies on the catalytic application of Hts, we be-
came interested in the possibility of their use as a dehydrohalogen-
ating agent for
a-bromo oximes or hydrazones 1. We were pleased
* Corresponding author. Tel.: +351 289 800 900x7619; fax: +351 289 819 403.
E-mail address: alemos@ualg.pt (A. Lemos).
to find that mixing the oxime or hydrazone with a 10 mass % of
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.045

1312
A. Lemos, J. P. Lourenço / Tetrahedron Letters 50 (2009) 1311–1313
be regarded as a valuable contribution to environmental friendly
and greener process.
YH
R2
Y
N
Y
X
base
- HX
N
N
R1
X
Further studies on the optimisation of the reaction conditions as
R
well the broadening the scope and application to other 4
Diels–Alder partners are underway.
p hetero
R
R
R1
R1
II
I
III
References and notes
R = CF3; CHO; COR3; CO2R4; C6H5; 4-NO2C6H4; P(O)(OR5)3; Me
R1 = H; Cl; P(O)(OR6)3; P(O)Ph3
1. Cavani, F.; Trefiro, F.; Vaccari, A. Catal. Today 1991, 11, 173–301.
2. Climent, M. J.; Corma, A.; Iborra, S.; Epping, K.; Velty, A. J. Catal. 2004, 225, 316–
326.
R2 = Br; Cl
Y = O; N-CO2R5; N-C6H4(NO2)2-2,4; N-SO2C6H4Me-4
X = NR7; O; CH2
3. Tichit, D.; Coq, B. Cattech 2003, 7, 206–217.
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Scheme 1. Synthesis of 1,2-oxazines and pyridazines by cycloaddition reactions of
nitroso- and azo-alkenes.
Table 1
Mg/Al Ht mediated [4+2] cycloadditionsa
Y
OEt
N
OEt
R
3a-c
YH
Br
Y
N
N
Base
O
R
R
Y
N
O
R
1
2
4a,b
Entry
R
Y
Base
Product
Yield (%)
(%)lit
1
2
3
4
5
6
7
8
9
CO2Et
CO2Et
Ph
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
O
O
O
Ht
Ht
Ht
Ht
Ht
—
Na2CO3
Htb
Htb
3a
4a
3b
3c
4b
—
54
21
48
80
58
—
—
51
82
(99)8h
(46)13
(87)14
(98)15
(100)15
9. Reviews: (a) Attanasi, O. A.; De Crescentini, L.; Filippone, P.; Mantelilini, F.;
Santeusanio, S. Arkivoc 2002, 274–292; (b) Attanasi, O. A.; Filippone, P. Synlett
1997, 1128–1140.
NCO2CMe3
NCO2CMe3
NCO2CMe3
NCO2CMe3
O
10. Recent contributions: (a) Lemos, A.; Lopes, M. Phosphorus, Sulfur Silicon Relat.
Elem. 2008, 183, 2882–2890; (b) Palácios, F.; Aparicio, D.; López, Y.; de los
Santos, J. M.; Alonso, C. Eur. J. Org. Chem. 2005, 6, 1142–1147; (c) Yang, H.-T.;
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43, 4351–4353; (e) Attanasi, O. A.; De Crescentini, L.; Filippone, P.; Fringuelli,
F.; Mantellini, F.; Matteucci, M.; Piermatti, O.; Pizzo, F. Helv. Chim. Acta 2001, 4,
513–525; (f) Boeckman, R. K., Jr.; Ge, P.; Reed, J. E. Org. Lett. 2001, 3, 3651–
3653; (g) Alves, C. N.; Romero, O. A. S.; da Silva, A. B. F. J. Mol. Struct. (Theochem)
2001, 535, 165–169; (h) Avalos, M.; Babiano, R.; Cintas, P.; Clemente, F. R.;
Gordillo, R.; Jiménez, J. L.; Palacios, J. C. J. Org. Chem. 2001, 66, 5139–5145; (i)
Atlan, V.; Buron, C.; Kaim, E. Synlett 2000, 489–490; (j) Zhang, L.; Williams, M.
A.; Mendel, D. B.; Escarpe, P. A.; Chela, X. Bioorg. Med. Chem. Lett. 1999, 9, 1751–
1756; (k) South, M. S. J. Heterocycl. Chem. 1999, 36, 306–319.
11. (a) Faragher, R.; Gilchrist, T. L. J. Chem. Soc., Chem. Commun. 1977, 252–253; (b)
Gilchrist, T. L.; Lingham, D. A.; Roberts, T. G. J. Chem. Soc., Chem. Commun. 1979,
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Commun. 1981, 696–698; (d) Nakanishi, S.; Shirai, Y.; Takahashi, K.; Otsuji, Y.
Chem. Lett. 1981, 869–872; (e) Gilchrist, T. L.; Iskander, G. M.; Yagoub, A. K. J.
Chem. Soc., Perkin Trans. 1 1985, 2769–2773; (f) Gilchrsit, T. L.; Hughes, D.;
Stretch, W. J. Chem. Soc., Perkin Trans. 1 1987, 2505–2509; (g) Christal, E. J. T.;
Gilchrist, T. L.; Stretch, W. J. Chem. Res. (S) 1987, 180–181; (h) Hippeli, C.;
Zimmer, R.; Reissig, H.-U. Liebigs Ann. Chem. 1990, 469–474; (i) Hippeli, C.;
Reissig, H.-U. Liebigs Ann. Chem. 1990, 475–481; (j) Arnold, T.; Orschel, B.;
Reissig, H.-U. Angew. Chem., Int. Ed. 1992, 31, 1033–1035; (k) Zimmer, R.;
Collas, M.; Roth, M.; Reissig, H.-U. Liebigs Ann. Chem. 1992, 709–714; (l)
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Hoffmann, M.; Reissig, H.-U. Chem. Ber. 1992, 125, 2243–2248; (n) Tiecco, M.;
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1993, 1989–1993; (o) Zimmer, R.; Arnold, T.; Homann, K.; Reissig, H.-U.
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1117; (q) Angermann, J.; Homann, K.; Reissig, H.-U.; Zimmer, R. Synlett 1995,
1014–1016; (r) Paulini, K.; Reissig, H.-U. Chem. Ber. 1994, 127, 685–689; (s)
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Streith, J.; Defoin, A. Synlett 1996, 189–200; (u) Zimmer, R.; Angermann, J.;
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—
3a
3c
NCO2CMe3
a
Reaction conditions: oxime or hydrazone (1 mmol), Mg/Al hydrotalcite (10%
mass equiv), dienophile (10 mmol), water (2 drops), rt, 16 h.
b
Regenerated and reused Mg/Al hydrotalcite.
calcinated hydrotalcite,16 in the presence of 10 mol equiv of dieno-
phile and two drops of water, afforded the expected cycloadducts
in reasonable to good yields (Table 1).17 The addition of water
was necessary, presumably to rehydrate the Ht, since in reactions
conducted in its absence no product could be detected or isolated.
Also, in control reactions performed in the absence of Ht, no
reaction products were detected (entry 6).
On replacing calcinated Mg:Al 3:1 Ht by sodium carbonate
under the same reaction conditions, that is, no solvent, 10 mass %
with or without two drops of water, no reaction products were iso-
lated (entry 7).
The Mg:Al 3:1 Ht filtered from the reaction media, washed with
water and acetone, dried and calcinated (500 °C under a flux of dry
air), could be used again without loss of activity (entries 8 and 9).
In summary, we have outlined a simple and effective method
for the generation of nitroso- and azo-alkenes by the catalytic
use of calcined Mg/Al 3:1 hydrotalcite and its cycloaddition reac-
tions with furan and ethyl vinyl ether, producing 5,6-dihydro-
4H-1,2-oxazines and 1,4,5,6-tetrhydropyridazines. The yields
obtained by this methodology, although somewhat lower than
those obtained by the commonly used strategy, are reasonable to
good. The advantages of the present methodology are the elimina-
tion of both organic solvent and large excess of an inorganic base.
Moreover, the ease of recovery and reuse of the hydrotalcite may

A. Lemos, J. P. Lourenço / Tetrahedron Letters 50 (2009) 1311–1313
1313
South, M. S.; Jakuboski, T. L.; Westmeyer, M. D.; Dukesherer, D. R. J. Org. Chem.
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5624.
80 °C overnight. Before the catalytic tests, the hydrotalcite was activated at 450
°C under a flux of dry nitrogen for 6 h.
17. Representative procedure for compound 3c: To the mixture of hydrazone 0.31
g (1 mmol) and ethyl vinyl ether (10 mmol), were added 0.03 g Ht (10 wt %)
and two drops of water. After stirring for 16 h, the Ht was filtered off. Dry-flash
chromatography of the filtrate (increasing polarity dichloromethane to
dichloromethane/ethyl acetate : 3/1) afforded the pyridazine 3c as a white
solid (0.24 g; 80%). mp: 65.8–67.4 (from hexanes; lit.13 mp 66–68 °C); 1H NMR
(400 MHz, CDCl3) d 5.58 (s, 1H), 4.36–4.12 (m, 2H), 3.55 (q, J = 6.9, 2H), 2.60
(dd, J = 5.8, 18.7, 1H), 2.50–2.33 (m, 1H), 2.05 (dd, J = 13.0, 19.3, 1H), 1.59 (d,
J = 62.8, 10H), 1.39–1.22 (m, 3H), 1.09 (t, J = 7.0, 3H); 13C NMR (101 MHz,
CDCl3) d 164.28, 152.33, 142.45, 82.93, 76.91, 63.73, 61.71, 28.19, 22.71, 17.47,
15.23, 14.21; IR (KBr cmꢀ1): 2998, 1711, 1607, 1335, 1270, 1159, 1080.
16. Procedure for Mg/Al hydrotalcite: A solution (100 mL) containing 0.1 mol of
Na2CO3 and 0.3 mol of NaOH was mixed (at a rate of 1 mL/min) with 100 mL of
a solution containing 0.111 mol of Mg(NO3)2 and 0.037 mol of Al(NO3)3 under
stirring at room temperature. The gel was left for 18
h at 80 °C. The
hydrotalcite was recovered by centrifugation, washed until pH 7 and dried at