Synergy between heterogeneous catalysis and microwave irradiation in an efficient one-pot synthesis of benzene derivatives via ring-opening of Diels-Alder cycloadducts of substituted furans

Article abstract of DOI:10.1055/s-2001-14580

The use of silica-supported Lewis acids as catalysts under microwave irradiation promotes regiospecific opening of the 7-oxa bridge of Diels-Alder cycloadducts, producing the corresponding arenes in a single step. This rapid and efficient procedure permits the synthesis of 1,2-, 1,2,4- and 1,2,3,4-substituted benzenes by reaction of 2,5-dimethylfuran (1), 2-methoxyfuran (2) and 2-ethylfuran (3) with dienophiles such as acrylonitrile, methyl acrylate, N-methylmaleimide and fumaronitrile.

Full text of DOI:10.1055/s-2001-14580

LETTER
753
Synergy between Heterogeneous Catalysis and Microwave Irradiation in an
Efficient One-Pot Synthesis of Benzene Derivatives via Ring-Opening of
Diels Alder Cycloadducts of Substituted Furans
Antonio de la Hoz,a* Angel Díaz-Ortiz,a José María Fraile,b María Victoria Gómez,a José Antonio Mayoral,b
Andrés Moreno,a* Alfonso Saiz,a Ester Vázqueza
a Facultad de Química, Universidad de Castilla-La Mancha, Campus Universitario, 13071 Ciudad Real, Spain
b ICMA-Facultad de Ciencias. Universidad de Zaragoza-CSIC. Pedro Cerbuna 12, E-50009 Zaragoza. Spain
Fax +34 926295318; E-mail: adlh@qino-cr.uclm.es
Received 22 March 2001
reasons we found it interesting to study the reactions of fu-
Abstract: The use of silica-supported Lewis acids as catalysts un-
ran derivatives with different dienophiles using heteroge-
neous catalysis assisted by microwave irradiation under
solvent-free conditions. Our aim was to achieve a reduc-
der microwave irradiation promotes regiospecific opening of the
7-oxa bridge of Diels Alder cycloadducts, producing the corre-
sponding arenes in a single step. This rapid and efficient procedure
permits the synthesis of 1,2-, 1,2,4- and 1,2,3,4-substituted ben- tion in the reaction times as well as to design an environ-
zenes by reaction of 2,5-dimethylfuran (1), 2-methoxyfuran (2) and
2-ethylfuran (3) with dienophiles such as acrylonitrile, methyl acry-
late, N-methylmaleimide and fumaronitrile.
mentally benign procedure avoiding the use of the
polluting homogeneous catalysts commonly used.
The catalysts used for these reactions were obtained by
Key words: furans, Diels Alder reactions, heterogeneous cataly-
treatment of silica with ZnCl2 [Si(Zn)],11 Et2AlCl
sis, microwaves, arenes
[Si(Al)]12 or TiCl4 [Si(Ti)].13 In the present paper a com-
parative study of the influence of the catalyst on the yield
of the aromatic compounds will be discussed.
Silica-supported Lewis acids are good catalysts for the Di-
els Alder reactions of furan derivatives with methyl acry-
late and acrylonitrile at room temperature.1 The resultant
7-oxabicyclo[2.2.1]heptenes are valuable synthetic inter-
mediates that have been further elaborated to substituted
arenes.2 Although these oxabicycles are easily prepared
through cycloaddition reactions of furans, and the oxygen
bridge can be removed by a variety of methods,3 only in a
few cases it is possible to obtain benzene derivatives in a
single step4,5 and usually a mixture of compounds is ob-
tained.6,3d Microwave radiation is an unconventional ener-
gy source whose usefulness in synthetic organic
chemistry has been increasingly recognised in recent
years.7 On the other hand, solvent-free conditions are es-
pecially suitable for microwave activation and several ad-
Scheme For compounds 8-15 see Table
vantages are evident for this approach.8 In the absence of
solvent the radiation is absorbed directly by the reagents,
As shown in the Scheme, furan derivatives undergo Di-
els Alder reactions with dienophiles (4 7) to give 7-ox-
abicyclo[2.2.1]hept-2-enes as intermediates. The
desorption of these intermediates would give the oxabicy-
cle compounds. However, under solvent-free conditions
this step is not easy and the co-ordination of the silica-sup-
ported catalyst with the oxygen bridge favours ring open-
ing, leading to aromatic products in only one step.
so the effect of microwaves is more marked. Moreover
solid supports can be used efficiently, many mineral ox-
ides are poor conductors of heat, while they absorb micro-
wave radiation very efficiently,9 this fact produces a real
benefit for supported reactions in microwave induced re-
actions. Thus, microwave irradiation has been applied
with success to cycloaddition reactions.10 As furan is an
acid-sensitive reagent, the rapid heating induced by mi-
crowave radiation leads to the formation of the products
under mild reaction conditions and with short reactions
times. This process avoids decomposition or side-reac-
tions and, in certain cases, increases the yields.
The process described here, owing to its procedural sim-
plicity and the use of readily available chemicals, appears
to be a promising and useful route to a wide variety of ar-
omatic compounds.
These kind of reactions have usually been performed in
two steps using homogeneous catalysis and, under these
conditions, long reactions times are required. For these
The reactions were performed in hermetically sealed Te-
flon tubes in a domestic microwave oven. The internal
pressures within the tubes were not measured. Reactions
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754
A. de la Hoz et al.
LETTER
Table One-pot synthesis of arenes catalysed by silica-supported Lewis acids using microwave irradiation or classical methods
a In all reactions a molar ratio furan derivative:dienophile of 6:1 and 0.5 g of silica-supported Lewis acids catalysts were used.
b All microwave reactions were carried out at 780 W.
c Reaction temperature was determined at the end of a blank reaction using microwave irradiation.
d In addition to this product, 10% of methyl 3-methoxybenzoate was obtained.
e In addition to this product, trace amounts of methyl 3-methoxybenzoate were detected.
Synlett 2001, No. 6, 753–756 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synergy between Heterogeneous Catalysis and Microwave Irradiation
755
were performed in the absence of solvent and reaction reactants. This method represents a simple, general and
conditions were optimised to obtain the best yield.14
useful alternative for the preparation of some polysubsti-
tuted benzenes whose synthesis is difficult by other meth-
ods.
The results of the study into the synthesis of arenes by mi-
crowave irradiation using silica-supported catalysts are
shown in the Table.
Further work is in progress to establish the precise mech-
anism of this ring opening in order to explain the high re-
gioselectivity observed.
We found that furan derivatives (1 3) react with different
dienophiles under microwave irradiation conditions with-
in 25 45 min, affording in one pot the aromatic products
indicated in the Table. The results obtained depend very
much on the reaction conditions, the nature of the Lewis
acid used as a catalyst, and the activation of the furan ring.
Acknowledgement
Financial support by the Spanish DGES (Project, PB97-0429) and
CICYT (Project MAT 1999-1176) and a predoctoral grant (E.V.)
are gratefully acknowledged.
Thus, the nature of the catalyst has, in some cases, a spec-
tacular effect on the yields. The use of Si(Ti) gives the
best results and the arene derivatives were obtained in
good to excellent yields. It is remarkable that the use of
SiO2 (entry 5) does not promote any reaction at all. This
result shows the importance of the catalytic activity of the
metal. Moreover, microwave irradiation plays an impor-
tant role in the reaction (see Table, entry 12 versus entry
13). The use of classical heating in an oil bath under com-
parable reaction conditions (temperature and reaction
time) leads to a dramatic decrease in the yield of the aro-
matic product.
References and Notes
(1) a) Fraile, J. M.; García, J. I.; Massam, J.; Mayoral, J. A.; Pires,
E. J. Mol. Catal. A 1997, 123, 43. b) Fraile, J. M.; García, J. I.;
Gracia, D.; Mayoral, J. A.; Pires, E. J. Org. Chem. 1996, 61,
9479.
(2) a) Campbell, M.M.; Kaye, A.D.; Sainsbury, M. Tetrahedron
Lett. 1983, 24, 4745. b) Campbell, M.M.; Kaye, A.D.;
Sainsbury, M.; Yavarzadeh, R. Tetrahedron Lett. 1984, 54,
1629.
(3) a) Hogeveen, H.; Middelkoop, T. B. Tetrahedron Lett. 1973,
3671. b) Hart, H.; Nwokogu, G. J. Org. Chem. 1981, 46, 1251.
c) Cochran, J. E.; Padwa, A. Tetrahedron Lett. 1995, 36, 3495.
d) Maggiani, A.; Tubul, A.; Brun, P. Tetrahedron Lett. 1998,
39, 4485.
(4) Padwa, A.; Dimitroff, M.; Waterson, A. G.; Wu, T. J. Org.
Chem. 1997, 62, 4088.
(5) Zhu, G.-D.; Staeger, M. A.; Boyd S. A. Org. Lett. 2000, 2,
3345.
(6) Brownbridge, P.; Chan, T.-H. Tetrahedron Lett. 1980, 21,
3423.
(7) a) Mingos, D. P. M.; Whittaker, A. G. Microwave Dielectric
Heating Effects in Chemical Synthesis in Chemistry under
Extreme or Non-Classical Conditions, (R. Eldik, C. D.
Hubbard, Eds.), Wiley, 1997. b) Caddick, C. Tetrahedron
1995, 52, 10403.
(8) a) Loupy, A.; Petit, A.; Hamelin, J.; Texier-Boullet, F.;
Jacquault, P.; Mathé, D. Synthesis 1998, 1213. b) Varma, R.S.
Green Chem. 1999, 1, 43.
(9) Loupy, A.; Bram, G.; Sansoulet, J. New J. Chem. 1992, 16,
233.
(10) de la Hoz, A.; Díaz-Ortiz, A.; Moreno, A.; Langa, F. Eur. J.
Org. Chem. 2000, 3659.
Usually the incorporation of an electron-donating group
in the 2-position of the furan has also been employed to
enhance the reactivity of the heteroaromatic ring sys-
tem.4,5 In our case, reactions involving 2-methoxyfuran
(2) exhibited a very high regioselectivity, with formation
of the more crowded compounds when asymmetric dieno-
philes were used (entries 16 and 20). Moreover, reaction
with fumaronitrile afforded 3-methoxyphthalonitrile in
excellent yield (entry 28). This fact could be related to the
stabilisation of the carbocation intermediate by the meth-
oxy group. It should be remarked that the previously re-
ported synthesis of phthalonitriles from furan derivatives
required a two-step procedure and ring opening of the cy-
cloadduct is usually performed in basic rather than acidic
conditions.13 On the other hand, the reaction of 2-ethylfu-
ran (3) with N-methylmaleimide demonstrated that this
reaction can be successful when less reactive furan deriv-
atives are used, albeit in moderate yields (entry 32).
Moreover, it should be noted that the treatment of the
three furan derivatives with N-methylmaleimide (6) gave
rise to new N-methylphthalimide derivatives,14 one of
which was obtained in quantitative yield (entry 12).
(11) Rhodes, C. N.; Brown, D. R. J. Chem. Soc., Faraday Trans.
1993, 89, 1387.
(12) a) Cativiela, C.; Fraile, J. M.; García, J. I.; Mayoral, J. A.;
Pires, E.; Royo, A. J.; Figueras, F. Tetrahedron 1993, 43,
4073. b) Cativiela, C.; Figueras, F.; García, J. I.; Mayoral, J.
A.; Pires, E.; Royo, A. J. Tetrahedron: Asymmetry 1993, 4,
621.
(13) a) Wong, H. N. C.; Ng, T.-K.; Wong, T.-Y. Heterocycles
1983, 20, 1815. b) Wong, H. N. C. Synthesis 1984, 787. c)
Wong, H. N. C.; Ng, T.-K.; Wong T.-Y.; Xing, Y. D.
Heterocycles 1984, 22, 875.
(14) Typical experimental procedure: A mixture of furan (1 3)
(9.0 mmol), an ethylenic dienophile (4 7) (1.5 mmol) and 0.5
g of silica-supported Lewis acid was charged to a commercial
25 mL Teflon PTFE vessel. The vessel was closed and
irradiated in a Miele Electronic M720 microwave oven for the
time and power indicated in the Table. In all reactions the
compounds were isolated by adding 50 mL of CH2Cl2 to the
In conclusion, the synthesis of a range of benzene deriva-
tives has proved to be possible using heterogeneous catal-
ysis under microwave irradiation. The advantage of using
microwave irradiation is not exclusively in the accelera-
tion of the reaction. Indeed, most compounds gave very
low yields when the reactions were performed using clas-
sical heating methods in an oil bath under comparable re-
action conditions (time and temperature). The products
are easily prepared in a single step by cycloaddition of
furans followed by ring opening of the oxabicyclo inter-
mediate by the action of Si(Ti). A variety of benzene de-
rivatives can be synthesised by choosing the appropriate
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756
A. de la Hoz et al.
LETTER
mixture and separating the catalyst by filtration. The solvent
was removed from the filtrate under reduced pressure and the
crude reaction mixtures were analysed by 1H and 13C NMR
spectroscopy in CDCl3. The products were purified by column
chromatography on silica gel (hexane/AcOEt 9:1 for
compounds 8, 9, 10 and 15, 3:1 for products 11 and 12, and 5:1
for 13 and 14). Yields were determined by 1H NMR
(15) McKeown, N. B.; Chambrier, I.; Cook, M. J., J. Chem. Soc.,
Perkin Trans. 1 1990, 1169.
(16) The physical and spectroscopic data for new synthetic
products. For compound 10: mp 168 169 ºC (from hexane),
MS (EI) m/z 189.1 (M+), 1H NMR (CDCl3, ): 2.63 (s, 6H, 3-
CH3, 6-CH3), 3.12 (s, 3H, NCH3), 7.28 (s, 2H, 4-H, 5-H) and
13C NMR (CDCl3, ): 17.3 (3-CH3, 6-CH3), 23.4 (NCH3),
129.0 (5-C, 4-C), 135.1 (3-C, 6-C), 135.8 (8-C, 9-C), 169.2
(2 CO). For compound 13: mp 123 125 ºC (from hexane),
MS (EI) m/z 191.0 (M+), 1H NMR (CDCl3, ): 3.14 (s, 3H,
NCH3), 4.03 (s, 3H, OCH3), 7.20 (d, J = 8.3 Hz, 1H, 4-H),
7.42 (d, J = 7.3 Hz, 1H, 6-H), 7.65 (dd, J = 7.3, 8.3 Hz, 1H, 5-
H) and 13C NMR (CDCl3, ): 23.7 (NCH3), 56.2 (OCH3),
115.2 (6-C), 117.3 (4-C), 134.3 (9-C), 135.9 (5-C), 156.4 (3-
C), 167.0 and 168.0 (2 CO). For compound 15: colourless
oil, bp 150 ºC (oven temperature) / 0.1mbar in a Kugelrohr
apparatus, MS (EI) m/z 189.1 (M+), 1H NMR (CDCl3, ): 1.29
(t, J = 7.6 Hz, 3H, CH3), 3.13 (q, J = 7.6 Hz, 2H, CH2), 3.16
(s, 3H, NCH3), 7.49 (d, J = 7.2 Hz, 1H, 4-H), 7.59 (t, J = 7.2
Hz, 1H, 5-H), 7.68 (d, J = 7.2 Hz, 1H, 6-H) and 13C NMR
(CDCl3, ): 14.9 (CH3), 23.7 (CH2), 24.5 (NCH3), 120.8 (5-C),
128.2 (6-C), 132.7 (4-C), 133.6 and 134.6 (8-C, 9-C), 144.2
(3-C), 168.5 and 169.1 (2 CO).
spectroscopy using CH2Br2 ( = 4.93 ppm) as an internal
standard. It should be remarked that for the reactions in entries
12 and 32 (Table) when the products are isolated the yields
present differences between 4% and 9% less than the
calculated yields using CH2Br2 as internal standard, this is a
proof of the accurancy of yields using this method. All
compounds were characterised by analytical methods and 1H
and 13C NMR, using mono- and two-dimensional
techniques.16 The new compounds exhibit NMR
spectroscopic properties consistent with their structures and
gave satisfactory molecular weight determinations (mass
spectrometry). Catalysts modified with Lewis acids were
obtained by treating silica gel with 1 M solutions of ZnCl2,
AlEt2Cl or TiCl4 following the previously described method.9-
11 The silica contained 1.5 mmol of Zn g−1, 1.4 mmol of Al
g−1 and 1.2 mmol of Ti g−1, respectively as determined by
plasma emission spectroscopy. For the Si(Zn) catalyst,
activation for 2 h at 150 ºC under vacuum was necessary
before use. Reactions by thermal heating were performed in an
oil bath under the same conditions of temperature and time as
the microwave reactions. This temperature was determined at
the end of a blank reaction using microwave irradiation.
Article Identifier:
1437-2096,E;2001,0,06,0753,0756,ftx,en;D00201ST.pdf
Synlett 2001, No. 6, 753–756 ISSN 0936-5214 © Thieme Stuttgart · New York