An efficient one-pot synthesis of phenol derivatives by ring opening and rearrangement of diels-alder cycloadducts of substituted furans using heterogeneous catalysis and microwave irradiation

Article abstract of DOI:10.1055/s-2004-825604

The use of silica-supported Lewis acids as catalysts under microwave irradiation promotes regiospecific opening of the 7-oxa bridge of Diels-Alder cycloadducts of furan derivatives and produces polysubstituted phenols in a single step. This rapid and effi

Full text of DOI:10.1055/s-2004-825604

LETTER
1259
An Efficient One-Pot Synthesis of Phenol Derivatives by Ring Opening and
Rearrangement of Diels–Alder Cycloadducts of Substituted Furans Using
Heterogeneous Catalysis and Microwave Irradiation
An
Efficient One-p
n
ot Synthesis
d
of Phenol
D
r
erivative
é
s
s Moreno,*a María Victoria Gómez,a Ester Vázquez,a Antonio de la Hoz,*a Angel Díaz-Ortiz,a Pilar Prieto,a
José Antonio Mayoral,b Elisabet Piresb
a
Facultad de Química, Universidad de Castilla-La Mancha, Campus Universitario, 13071 Ciudad Real, Spain
Fax +34(926)295318; E-mail: antonio.hoz@uclm.es
b
ICMA-Facultad de Ciencias, Universidad de Zaragoza-CSIC, Pedro Cerbuna 12, 50009 Zaragoza, Spain
Received 14 November 2003
Recently, we reported the reaction of 2,5-dimethylfuran,
Abstract: The use of silica-supported Lewis acids as catalysts
under microwave irradiation promotes regiospecific opening of the
7-oxa bridge of Diels–Alder cycloadducts of furan derivatives and
produces polysubstituted phenols in a single step. This rapid and
2-methoxyfuran and 2-ethylfuran with dienophiles such
as acrylonitrile, methyl acrylate, N-methylmaleimide and
fumaronitrile using heterogeneous catalysis under micro-
efficient procedure permits the synthesis of tri-, tetra- and penta- wave irradiation.7 The use of silica-supported Lewis acids
substituted benzene derivatives by reaction of 2,5-dimethylfuran
(1), 2-ethylfuran (2) and 2-methoxyfuran (3) with dienophiles such
as catalysts allows benzene derivatives to be obtained in a
single step by regiospecific opening of the 7-oxa bridge of
as dimethyl acetylenedicarboxylate and methyl propiolate.
Diels–Alder cycloadducts.
Key words: furans, Diels–Alder reactions, heterogeneous cataly-
Another class of dienophile that undergoes Diels–Alder
sis, microwaves, phenol derivatives
cycloaddition to furans are alkynes that possess at least
one electron-withdrawing group. The resultant 7-oxabicy-
clo[2.2.1]hept-2,5-dienes are valuable synthetic interme-
Silica-supported Lewis acids are good catalysts for Diels–
diates that have been further elaborated to substituted
Alder reactions between furan and acrylonitrile or methyl
arenes.8 These arene 1,4-endoxides are easily prepared
acrylate at room temperature.1 When 2,5-dimethylfuran is
through cycloaddition reactions of furans and the oxygen
used as the diene, yields of the Diels–Alder adducts with
bridge can be removed by a variety of methods.9 Howev-
methyl acrylate are lower, due in part to the appearance of
er, only in a few cases is it possible to obtain phenol de-
aromatisation products.2
rivatives in a single step10 and a mixture of compounds is
usually formed.11
Microwave radiation is an unconventional energy source
whose utility in synthetic organic chemistry has been in-
creasingly recognised in recent years.3 On the other hand,
solvent-free conditions are especially suitable for micro-
wave activation and several advantages are evident for
this approach.4 In the absence of solvent the radiation is
absorbed directly by the reagents, so the effect of micro-
waves is more marked. Moreover, solid supports can be
used efficiently; many mineral oxides are poor conductors
of heat but they absorb microwave radiation very effi-
ciently,5 a situation that produces a real benefit in support-
ed reactions induced by microwaves. In this respect,
microwave irradiation has been applied with success to
cycloaddition reactions.6 Furan is an acid-sensitive
reagent and so the rapid heating induced by microwave
radiation leads to the formation of the desired products
under mild reaction conditions and with short reaction
times. This process avoids decomposition or side-reac-
tions and, in certain cases, increases the yields.
These kinds of reactions are usually performed in two
steps using homogeneous catalysis and, under these con-
ditions, long reaction times are required. For this reason
we found it of interest to study the reactions of furan
derivatives with alkynes using heterogeneous catalysis
assisted by microwave irradiation under solvent-free con-
ditions. It was envisaged that this approach could provide
a general method to obtain the phenol derivatives in a
single step. Our aim was to achieve a reduction in the
reaction times as well as to design an environmentally
benign procedure that avoids the use of the polluting
homogeneous catalysts that are commonly employed.
The catalysts used for these reactions were obtained by
treatment of silica with ZnCl2 [Si(Zn)],12 Et2AlCl
[Si(Al)]13 or TiCl4 [Si(Ti)].13 In the present paper a com-
parative study of the influence of the catalyst on the yield
of the phenolic compounds will be discussed.
As shown in Scheme 1, furan derivatives undergo Diels–
Alder reactions with dienophiles (4 and 5) to give 7-oxa-
bicyclo[2.2.1]hept-2,5-dienes as intermediates. The
desorption of these intermediates would give the oxabicy-
clic compounds. However, under solvent-free conditions
this step is not easy and the coordination of the silica-
supported catalyst with the oxygen bridge favours ring
SYNLETT 2004, No. 7, pp 1259–1263
Advanced online publication: 19.05.2004
DOI: 10.1055/s-2004-825604; Art ID: D27303ST
© Georg Thieme Verlag Stuttgart · New York
0
3.
0
6.
2
0
0
4

1260
A. Moreno et al.
LETTER
OH
X
O
Y
R1
X
R1
R2
O
X
MW
R1
+
Si(M)
R2
Y
R2
Y
6–11
1–3
4–5
1: X=Y=CH3; 2: X=H, Y=CH2CH3 ; 3: X=H, Y=OCH3
4: R1= R2=COOCH3, 5: R1=COOCH3, R2=H
For compounds 6–11 see Table 1.
Scheme 1
opening, leading to phenolic products in only one step. atives indicated in Table 1. The results obtained depend
Although this conversion can be useful, it can also be very much on the reaction conditions, the nature of the
complex when other substituents are present. The reaction Lewis acid catalyst, and the activation and substitution of
conditions described here give rise to only one product.
the furan ring.
The process described here, owing to its procedural sim- The nature of the catalyst has, in some cases, a spectacular
plicity and the use of readily available chemicals, appears effect on the yields. The use of Si(Zn) gives the best
to be a promising and useful route to a wide variety of results and the phenolic derivatives were obtained in mod-
polysubstituted phenolic compounds. The reactions were erate to good yields (see Table 1, entry 1 vs entry 3 and
performed in hermetically sealed Teflon tubes in a domes- entry 13 vs entry 15). These results can be explained in
tic microwave oven. The internal pressures within the terms of the different acid characteristics of the catalyst –
tubes were not measured. Reactions were performed in Si(Zn) is a pure Lewis acid but Si(Al) and Si(Ti) have
the absence of solvent and reaction conditions were opti- Lewis/Brønsted acid area ratios15 of 5.3 and 4.4, respec-
mised to obtain the best yield.14 The results of the study tively. Moreover, in some cases the use of classical heat-
into the synthesis of phenol derivatives by microwave ir- ing in an oil bath under comparable reaction conditions
radiation using silica-supported catalysts are shown in (temperature and reaction time) leads to a dramatic de-
Table 1.
crease in the yield of the phenolic product (see Table 1,
entry 3 vs entry 4).
We found that furan derivatives (1–3) react with dieno-
philes (4 and 5) under microwave irradiation conditions
within 30 minutes, affording in one pot the phenol deriv-
Table 1 One-pot Synthesis of Phenols Catalysed by Silica-supported Lewis Acids Using Microwave Irradiation or Classical Methods
Entry Diene
Dienophile
Catalyst
Reaction conditionsa
Product
Yield (%)d
Microwave
irradiationb
Thermal
heatingc
1
2
3
4
Si(Ti)
Si(Al)
Si(Zn)
Si(Zn)
30 min
30 min
30 min
33 (22)e
25 (32)e
65
CH3
O
OH
COOCH3
H3C
COOCH3
COOCH3
30 min, 90 °C
18
COOCH3
CH3
4
CH3
OH
1
6
5
6
7
8
Si(Ti)
Si(Al)
Si(Zn)
Si(Zn)
30 min
30 min
30 min
11
18
22
21
CH3
O
COOCH3
H3C
COOCH3
30 min, 90 °C
5
CH3
CH3
1
7
Synlett 2004, No. 7, 1259–1263 © Thieme Stuttgart · New York

LETTER
An Efficient One-Pot Synthesis of Phenol Derivatives
1261
Table 1 One-pot Synthesis of Phenols Catalysed by Silica-supported Lewis Acids Using Microwave Irradiation or Classical Methods
(continued)
Entry Diene
Dienophile
Catalyst
Reaction conditionsa
Product
Yield (%)d
Microwave
irradiationb
Thermal
heatingc
9
10
11
12
Si(Ti)
Si(Al)
Si(Zn)
Si(Zn)
30 min
30 min
30 min
46
53
66
68
COOCH3
CH2CH3
O
OH
COOCH3
COOCH3
30 min, 105 °C
COOCH3
2
4
CH2CH3
8
13
14
15
16
Si(Ti)
Si(Al)
Si(Zn)
Si(Zn)
30 min
30 min
30 min
10
17
56
28
COOCH3
OH
CH2CH3
O
COOCH3
30 min, 100 °C
30 min, 100 °C
30 min, 100 °C
5
2
CH2CH3
OH
9
17
18
19
20
Si(Ti)
Si(Al)
Si(Zn)
Si(Zn)
30 min
30 min
30 min
65
27
81
87
COOCH3
OCH3
O
COOCH3
COOCH3
COOCH3
3
4
OCH3
OH
10
21
22
23
24
Si(Ti)
Si(Al)
Si(Zn)
Si(Zn)
30 min
30 min
30 min
35 (15)f
34 (24)f
25 (19)f
26 (10)f
OCH3
O
COOCH3
5
COOCH3
3
OCH3
11
a In all reactions a 6:1 molar ratio of furan derivative:dienophile and 0.5 g of silica-supported Lewis acids catalysts were used.
b All microwave reactions were carried out at 450 W.
c Reactions carried out 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.
d The yields were determined by 1H NMR spectroscopy using CH2Br2 as an internal standard (see ref.14).
e In addition the arene 1,4-endoxide was obtained (yields in parentheses).
f In addition to main product, the corresponding methoxy derivative (methyl 2,5-dimethoxybenzoate) was obtained.
A rearrangement reaction does not necessarily take place these reactions can be successful when less reactive furan
when monosubstituted furans are used in the aromatisa- derivatives, such as 2-ethylfuran (2), are used (entry 11
tion of the adduct, a situation that explains why only in and 15).
reactions involving dimethylfuran is the corresponding
The incorporation of an electron-donating group in the 2-
adduct detected. Thus, reactions involving 2-ethylfuran
position of the furan has also been employed to enhance
(2) exhibited a very high regioselectivity, with the forma-
the reactivity of the heteroaromatic ring system.10 In our
case, reactions involving 2-methoxyfuran (3) and dimeth-
yl acetylenedicarboxylate (4) gave 2,3,4-trisubstituted
phenol derivatives in very good yield and with a very high
tion of 2,4-disubstituted phenol derivatives when methyl
propiolate was used as an asymmetric dienophile (entry
15). Moreover, the reaction of 2 with dimethyl acetylene-
dicarboxylate and methyl propiolate demonstrated that
regioselectivity that is in complete agreement with the
Synlett 2004, No. 7, 1259–1263 © Thieme Stuttgart · New York

1262
A. Moreno et al.
LETTER
(4) (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.
(5) Loupy, A.; Bram, G.; Sansoulet, J. New J. Chem. 1992, 16,
233.
calculated atomic coefficients. The calculated atomic co-
efficients in the frontier molecular orbital using the
AMPAC program16 with the RHF/AM1 method are
shown in Figure 1.
(6) de la Hoz, A.; Díaz-Ortiz, A.; Moreno, A.; Langa, F. Eur. J.
Org. Chem. 2000, 3659.
(7) de la Hoz, A.; Díaz-Ortiz, A.; Fraile, J. M.; Gómez, M. V.;
Mayoral, J. A.; Moreno, A.; Saiz, A.; Vazquez, E. Synlett
2001, 753.
OH
0.5691
O
–0.5726
COOCH3
CH2CH3
2
(8) (a) Hart, H.; Nwokogu, G. J. Org. Chem. 1981, 46, 1251.
(b) Huang, N. Z.; Xing, Y. D.; Xe, D. Y. Synthesis 1982,
1041. (c) Xing, Y. D.; Huang, N. Z. J. Org. Chem. 1982, 47,
140. (d) Wong, H. N. C.; Ng, T.-K.; Wong, T.-Y.
Heterocycles 1983, 20, 1815. (e) Wong, H. N. C.; Xing, Y.
D.; Zhou, Y. F.; Gong, Q. Q.; Zhang, C. Synthesis 1984,
787. (f) Wong, H. N. C.; Ng, T.-K.; Wong, T.-Y.; Xing, Y.
D. Heterocycles 1984, 22, 875.
0.5891 –0.4193
9
COOCH3
0.5470
CH2CH3
OH
5
O
–0.4799
MO
Si(M)
C- OCH3
3
11
(9) (a) Chambers, R. D.; Roche, A. J.; Rock, M. H. J. Chem.
Soc., Perkin Trans. 1 1996, 1095. (b) Martin-Matute, B.;
Nevado, C.; Cardenas, D. J.; Echavarren, A. M. J. Am.
Chem. Soc. 2003, 125, 5757.
COOCH3
OCH3
(10) (a) Padwa, A.; Dimitroff, M.; Waterson, A. G.; Wu, T. J.
Org. Chem. 1997, 62, 4088. (b) Zhu, G.-D.; Staeger, M. A.;
Boyd, S. A. Org. Lett. 2000, 2, 3345.
Figure 1
(11) (a) Maggiani, A.; Tubul, A.; Brun, P. Synthesis 1997, 631.
(b) Maggiani, A.; Tubul, A.; Brun, P. Tetrahedron Lett.
1998, 39, 4485.
(12) Rhodes, C. N.; Brown, D. R. J. Chem. Soc., Faraday Trans.
1993, 89, 1387.
(13) (a) Cativiela, C.; Fraile, J. M.; García, J. I.; Mayoral, J. A.;
Pires, E.; Royo, A. J.; Figueras, F.; de Mérnoval, L. C.
Tetrahedron 1993, 49, 4073. (b) Cativiela, C.; Figueras, F.;
García, J. I.; Mayoral, J. A.; Pires, E.; Royo, A. J.
Tetrahedron: Asymmetry 1993, 4, 621.
In conclusion, the synthesis of a range of phenolic deriva-
tives has been achieved using heterogeneous catalysis
under microwave irradiation. The products are easily pre-
pared in a single step by cycloaddition of furans followed
by ring opening of the oxabicyclo intermediate through
the action of Si(Zn). A variety of phenolic derivatives can
be synthesised by selecting the appropriate reactants. This
method represents a simple, general and useful alternative
for the preparation of some polysubstituted phenols
whose synthesis is difficult by other methods.
(14) Typical Experimental Procedure: A mixture of furan (1–
3, 9.0 mmol), an acetylenic dienophile (4 and 5, 1.5 mmol)
and silica-supported Lewis acid (0.5 g) was charged to a
commercial 25 mL Teflon PTFE vessel. The vessel was
closed and irradiated in a Miele Electronic M720 microwave
oven at 450 W during 30 min. In all reactions the compounds
were isolated by adding 50 mL of CH2Cl2 to the mixture and
separating the catalyst by filtration. The solvent was
removed from the filtrate under reduced pressure and the
Computational studies are in progress in order to explain
the observed high regioselectivity.
Acknowledgment
Financial support from the Spanish DGESIC (Project, BQU2001-
1095 and PPQ2002-04012-C03-01) and Junta de Comunidades de
Castilla-La Mancha (Project PAI-02-019) is gratefully acknowled-
ged. One of us (V. G.) wishes to acknowledge a grant from Spanish
MECD.
crude reaction mixtures were analysed by 1H NMR and 13
C
NMR spectroscopy in CDCl3. The products were purified by
column chromatography on silica gel (hexane–EtOAc 8:1
for compound 9 and 3:1 for product 11)17 or by distillation
under reduced pressure in a Kugelrohr apparatus (for
compounds 6,18 7,19 8 and 1020). Yields were determined by
1H NMR spectroscopy using CH2Br2 (d = 4.93 ppm) as an
internal standard. It should be remarked that for the reactions
in entries 15 and 23 (Table 1) the isolated yields show
differences of between 3% and 7% less than the calculated
yields using CH2Br2 as internal standard, thus demonstrating
the accuracy of this method. All compounds were
References
(1) (a) Fraile, J. M.; García, J. I.; Massam, J.; Mayoral, J. A.;
Pires, E. J. Mol. Catal. A: Chem. 1997, 123, 43. (b) Fraile,
J. M.; García, J. I.; Gracia, D.; Mayoral, J. A.; Pires, E. J.
Org. Chem. 1996, 61, 9479.
(2) Fraile, J. M.; García, J. I.; Gómez, M. A.; de la Hoz, A.;
Mayoral, J. A.; Moreno, A.; Prieto, P.; Salvatella, L.;
Vazquez, E. Eur. J. Org. Chem. 2001, 2891.
(3) (a) Mingos, D. P. M.; Whittaker, A. G. Microwave
Dielectric Heating Effects in Chemical Synthesis, In
Chemistry under Extreme or non-Classical Conditions;
Eldik, R.; Hubbard, C. D., Eds.; Wiley: New York, 1997.
(b) Caddick, S. Tetrahedron 1995, 52, 10403. (c) Lidström,
P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001,
57, 9225. (d) Microwaves in Organic Synthesis; Loupy, A.,
Ed.; Wiley-VCH: Weinheim, 2002.
characterised by analytical methods and 1H NMR and 13
NMR spectroscopy, using one- and two-dimensional
techniques. The new compounds exhibit NMR spectra
consistent with their structures and gave satisfactory
molecular weight determinations (mass spectrometry).21
Catalysts modified with Lewis acids were obtained by
C
treating silica gel with 1 M solutions of ZnCl2, AlEt2Cl or
TiCl4 following the previously described method.12,13 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
Synlett 2004, No. 7, 1259–1263 © Thieme Stuttgart · New York

LETTER
for 2 h at 150 °C under vacuum was necessary before use.
An Efficient One-Pot Synthesis of Phenol Derivatives
1263
(19) Snider, B. B.; Patricia, J. J. J. Org. Chem. 1989, 54, 38.
(20) Keay, B. A.; Rodrigo, R. Tetrahedron 1984, 40, 4597.
(21) The physical and spectroscopic data for the new synthetic
compounds. Compound 8: yellow oil, bp 225 °C (oven
temperature)/0.1 mbar in a Kugelrohr apparatus. MS (EI):
m/z = 238 [M+]. 1H NMR (CDCl3): d = 1.18 (t, J = 7.6 Hz,
3 H, -CH2CH3), 2.50 (q, J = 7.6 Hz, 2 H, -CH2CH3), 3.80 (s,
3 H, 1-COOCH3), 3.84 (s, 3 H, 2-COOCH3), 7.0 (d, J = 8.4
Hz, 1 H, 4-H), 7.34 (d, J = 8.4 Hz, 1 H, 5-H), 10.83 (s, 1 H,
-OH). 13C NMR (CDCl3): d = 17.0 (-CH3), 27.0 (-CH2-),
52.0 (1-OCH3), 53.0 (2-OCH3), 108.2 (2-C), 119.3 (4-C),
132.0 (6-C), 134.0 (1-C), 136.0 (5-C), 159.8 (3-C), 169.3,
169.4 (1-COO, 2-COO). Compound 9: yellow oil. MS (EI):
m/z = 180 [M+], 1H NMR (CDCl3): d = 1.18 (t, J = 7.6 Hz,
3 H, -CH2CH3), 2.88 (q, J = 7.6 Hz, 2 H, -CH2CH3), 3.88 (s,
3 H, 1-COOCH3), 6.40 (s, 1 H, -OH), 6.97 (dd, J = 8.3 Hz,
J = 2.7 Hz, 1 H, 3-H), 7.12 (d, J = 8.3 Hz, 1 H, 4-H), 7.38 (d,
J = 2.7 Hz, 1 H, 6-H). 13C NMR (CDCl3): d = 16.0 (-CH3),
27.8 (-CH2-), 52.0 (1-OCH3), 117.9 (6-C), 120.0 (3-C),
130.0 (1-C), 132.0 (4-C), 138.0 (5-C), 153.9 (2-C), 168.2
Reactions carried out using 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.
(15) The modified silicas were characterised by IR spectroscopy.
Pyridine adsorption-desorption experiments were carried
out in order to determine the relative proportion of Lewis
and Brønsted acidic sites. Thus, Lewis/Brønsted acid area
ratios were determined by the integral areas of Lewis and
Brønsted IR bands of pyridine adsorbed onto modified
silicas previously described by: Fraile, J. M.; García, J. I.;
Mayoral, J. A.; Pires, E.; Salvatella, L.; Ten, M. J. Phys.
Chem. B 1999, 103, 1664.
(16) Program AMPAC, v. 7.0 Semichem, Inc. 2000.
(17) Schmidt, U.; Boekens, H.; Lieberknecht, A.; Griesser, H.
Liebigs Ann. Chem. 1983, 9, 1459.
(18) Newman, M. S.; Chung, H. M. J. Org. Chem. 1974, 39,
1036.
Synlett 2004, No. 7, 1259–1263 © Thieme Stuttgart · New York