[AlCl3 + 2THF]: A new and efficient catalytic system for Diels-Alder cycloaddition of α,β-unsaturated carbonyl compounds under solvent-free conditions

Article abstract of DOI:10.1021/ol060569q

[AlCl₃ + 2THF] is a new catalytic system for the Diels-Alder cycloaddition under SFC and air atmosphere. By using equimolar amounts of reactants, this catalyst prevents the polymerization of the diene and allows the corresponding adducts to be isolated with high regio- and stereocontrol and in excellent yields.

Full text of DOI:10.1021/ol060569q

ORGANIC
LETTERS
2006
Vol. 8, No. 12
2487-2489
[AlCl3
Catalytic System for Diels
Cycloaddition of -Unsaturated
Carbonyl Compounds under
Solvent-Free Conditions
+
2THF]: A New and Efficient
−Alder
r,â
Francesco Fringuelli,* Rugiada Girotti, Ferdinando Pizzo,* and Luigi Vaccaro
CEMIN, Centro di Eccellenza Materiali InnoVatiVi Nanostrutturati, Dipartimento di
Chimica, UniVersita` di Perugia, Via Elce di Sotto 8, I-06123 Perugia, Italy
frifra@unipg.it; pizzo@unipg.it
Received March 8, 2006
ABSTRACT
[AlCl3
+ 2THF] is a new catalytic system for the Diels−Alder cycloaddition under SFC and air atmosphere. By using equimolar amounts of
reactants, this catalyst prevents the polymerization of the diene and allows the corresponding adducts to be isolated with high regio- and
stereocontrol and in excellent yields.
The Diels-Alder cycloaddition is one of the best known
processes in organic chemistry and has been carried out under
a variety of reaction conditions, mainly in organic solvent
and in the presence of a catalyst.1
The use of SFC is playing an important role in the
development of modern and green organic synthesis.4 There
is a growing number of examples in which the rate, the
selectivity, and the yields obtained under SFC are better than
those obtained in organic solvent.2,4,5
Surprisingly, this reaction has been scarcely investigated
under solvent-free conditions (SFC).1 To our knowledge, only
one example of Lewis acid-catalyzed hetero-Diels-Alder of
aromatic aldehydes with the highly reactive Danishefsky’s
diene has been reported under SFC to date.2
In the past few years, we have been contributing in the
development of organic processes in water6 and under SFC.5
According to this research and to our continuous efforts to
study Diels-Alder cycloadditions,1a-c we have started a
It is known that a Lewis acid catalyst activates the
dienophile but also favors the polymerization of the diene,
and consequently, an excess of diene is generally used to
achieve the complete conversion of the dienophile.3
(3) Cationic polymerization of a diene is catalyzed by Lewis acids, such
as AlCl3: Elias, G.-H. An Introduction to Polymer Science; Wiley-VCH:
Weinheim, Germany, 2005; p 73.
(4) (a) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and
Practice; Oxford University Press: Oxford, 1998. (b) Metzger, J. O. Angew.
Chem., Int. Ed. 1998, 37, 2975-2978. (c) Tanaka, K.; Toda, F. Chem. ReV.
2000, 100, 1025-1074. (d) Varma, R. S. Pure Appl. Chem. 2001, 73, 193-
198. (f) Cave, G. W. V.; Raston, C.; Scott, J. L. Chem. Commun. 2001,
2159-2169. (e) Toda, F. SolVent-free Organic Synthesis; Wiley-VCH:
Weinheim, Germany, 2003.
(5) For some recent examples from our group, see: (a) Fringuelli, F.;
Pizzo, F.; Tortoioli, S.; Vaccaro, L. J. Org. Chem. 2004, 69, 8780-8785.
(b) Fringuelli, F.; Pizzo, F.; Vittoriani, C.; Vaccaro, L. Chem. Commun.
2004, 2586-2687. (c) Amantini, D.; Fringuelli, F.; Piermatti, O.; Pizzo,
F.; Zunino, E.; Vaccaro, L. J. Org. Chem. 2005, 70, 6526-6529.
(1) (a) Fringuelli, F.; Taticchi, A. Dienes in the Diels-Alder Reaction;
John Wiley & Sons: New York, 1990. (b) Fringuelli, F.; Piermatti, O.;
Pizzo, F.; Vaccaro, L. Eur. J. Org. Chem. 2001, 439-457. (c) Fringuelli,
F.; Taticchi, A. The Diels-Alder Reaction: Selected Practical Methods;
John Wiley & Sons: Chichester: UK, 2002. (d) Cycloaddition Reactions
in Organic Synthesis; Kobayashi, S., Jørgensen, K., Eds; Wiley-VCH:
Weinheim, Germany, 2002.
(2) Long, J.; Hu, J.; Shen, X.; Ji, B.; Ding, K. J. Am. Chem. Soc. 2002,
124, 10-11.
10.1021/ol060569q CCC: $33.50
© 2006 American Chemical Society
Published on Web 05/19/2006

project aimed at defining a general protocol for realizing this
important reaction under environmentally friendly conditions.
Considering our previous interest in the use of AlCl3 in
the Diels-Alder cycloaddition of R,â-cycloalkenones in
organic solvents,7d we intend to investigate this process under
SFC.
Table 1. [AlCl3 + 2THF]-Catalyzed Diels-Alder Reaction of
Ethyl Acrylate (1a) with Isoprene (2) under SFC at 30 °C
Since Yates and Eaton’s pioneering work in the 1960s,7a
AlCl3 has been known as an efficient catalyst for the Diels-
Alder cycloaddition of R,â-unsaturated carbonyl com-
pounds,1,7 but in the past decade, its use has been made less
frequent due to its very high acidity, which is responsible
for the significant polymerization of the diene and/or the
dienophile.7b-e
We maintain that by lowering the Lewis acidity of AlCl3,
while increasing the reactivity by using SFC, it is possible
to avoid the polymerization of the diene and the dienophile
allowing the use of stoichiometric amounts of reagents. We
planned to realize the Diels-Alder cycloadditions of R,â-
unsaturated esters, ketones, aldehydes, anhydrides, and
amides with 1,3-butadienes by operating (a) under SFC, (b)
at room temperature, and (c) with equimolar amounts of
diene and dienophile that it is possible only if polymerization
of the diene is avoided.
In this communication, we report the results of the Diels-
Alder cycloadditions of dienes 2, 4, and 5 with dienophiles
1a-l catalyzed by AlCl3 catalysts.
We initially performed the reaction of ethyl acrylate (1a)
with isoprene (2) (equimolar amounts) under SFC at 30 °C
in the presence of 5 mol % of AlCl3. The conversion of 1a
to cycloadduct 3a after 12 h was 80% (Table 1, entry 1).
The reaction did not reach completion because 20% of
isoprene (2) polymerized.
entry
catalyst
AlCl3
[AlCl3 + 1THF]
[AlCl3 + 2THF]
[AlCl3 + 3THF]
[AlCl3 + 4THF]
AlCl3 in THF
Ca (%)
polymerization (%)b
1
2
3
4
5
6
7
8
9
80
83
>99c
70
37
-
20
-
-
20
17
-
-
-
-
-
-
-
[AlCl3 + 1DEG]
[AlCl3 + 2DES]
[AlCl3 + 2TEA]
a C ) Conversion (determined by H NMR analysis). b Polymerization
was evaluated by 1H NMR analysis by using p-nitroanisole as internal
standard. c Isolation yield ) 92%.
1
tion of AlCl3 and 3 or 4 equiv of THF, the process was
significantly slower (Table 1, entries 4 and 5). Expectedly,
when THF was used as reaction medium, adduct 3a was not
detected at all (Table 1, entry 6).
The catalytic activity of AlCl3 was reduced in the presence
of 1 equiv of DEG, while it was completely depressed by 2
equiv of DES or TEA (Table 1, entries 7-9).
The effect of THF in the AlCl3-catalyzed reaction of
equimolar amounts of 3-hepten-2-one (1b) with isoprene (2)
is even more evident (Scheme 1). In fact, in the absence of
It is known that the catalytic ability of the Lewis acid can
be strongly influenced by using ligands, such as ethers,
thioethers, and amines.8 Therefore, to carry the AlCl3-
catalyzed cycloaddition of 1a and 2a to completion, we
employed tetrahydrofuran (THF), diethylene glycol (DEG),
diethyl sulfide (DES), and triethylamine (TEA) as represen-
tative ligands.
Scheme 1. [AlCl3 + 2THF]-Catalyzed Cycloadditions of
3-Hepten-2-one (1b) with Isoprene (2) under SFC at 30 °C
Equimolar amounts of 1a and 2 were added at 30 °C to 5
mol % of a 1:2 mixture of AlCl3 and THF ([AlCl3 + 2THF])
under air atmosphere. After 12 h, the adduct 3a was formed
in a 95:5 para:meta ratio, and it was isolated in an almost
quantitative yield (Table 1, entry 3). When the reaction was
carried out with 5 mol % of [AlCl3 + 1THF], no positive
effect was detected (Table 1, entry 2). By using a combina-
THF, only 35% conversion was reached after 1 h and the
polymerization of 2 was mainly obtained, while a complete
conversion to 3b was accomplished in the presence of 2 equiv
of THF.
AlCl3‚THF9a and AlCl3‚2THF9b are known complexes. We
have not identified the actual catalytic species acting in the
reactions of 1a and 1b with 2, and therefore, we refer to a
catalytic system identified as [AlCl3 + 2THF], indicating
that we have used AlCl3 and THF in a 1:2 molar ratio.
The catalytic efficiency of [AlCl3 + 2THF] was confirmed
in the cycloadditions of 1a with 1,3-dienes 4 and 5 (Scheme
(6) For recent papers, see: (a) Fringuelli, F.; Pizzo, F.; Rucci, M.;
Vaccaro, L. J. Org. Chem. 2003, 68, 7041-7045. (b) Amantini, D.;
Fringuelli, F.; Piermatti, O.; Pizzo, F.; Vaccaro, L. J. Org. Chem. 2003,
68, 9263-9268. (c) Fringuelli, F.; Pizzo, F.; Tortoioli, S.; Vaccaro, L. Org.
Lett. 2005, 7, 4411-4414.
(7) (a) Yates, P.; Eaton, P. J. Am. Chem. Soc. 1960, 82, 4436-4437. (b)
Inumai, T.; Kojima, T. J. Org. Chem. 1966, 31, 1121-1123. (c) Inumai,
T.; Kojima, T. J. Org. Chem. 1970, 35, 1342-1348. (d) Fringuelli, F.; Guo,
M.; Pizzo, F.; Taticchi, A.; Wenkert, E. J. Org. Chem. 1989, 54, 710-712
(part 16). (e) Bueno, M. P.; Cativiela, C. A.; Mayoral, J. A. J. Org. Chem.
1991, 56, 6551-6555. (f) Shing, T. K. M.; Lo, H. Y.; Mak, T. C. W.
Tetrahedron 1999, 55, 4643-4648. (g) Yin, D.; Yin, D.; Fu, Z.; Li, Q. J.
Mol. Catal. A 1999, 148, 87-95.
(9) (a) Deroualt, J.; Granger, P.; Forel, M. T. Inorg. Chem. 1977, 16,
3214-3218. (b) Cowley, A. H.; Cushner, M. C.; Davis, R. E.; Riley, P. E.
Inorg. Chem. 1981, 20, 1179-1181.
(8) Lewis Acids in Organic Synthesis; Yamamoto, H., Ed.; Wiley-VCH:
Weinheim, Germany, 1999.
2488
Org. Lett., Vol. 8, No. 12, 2006

2). In the presence of 2.5 or 5 mol % of [AlCl3 + 2THF],
Table 2. [AlCl3 + 2THF]-Catalyzed Diels-Alder Reactions of
Dienophiles 1c-l with Isoprene (2)10
Scheme 2. [AlCl3 + 2THF]-Catalyzed Diels-Alder
Cycloadditions of 1a with 1,3-Butadienes 4 and 5 at 30 °C
and by using equimolar amounts of reagents, the cycload-
ducts 4a and 5a were isolated in 82 and 80% yields,
respectively. The stereoselectivity was high in the case of
cyclopentadiene (5) where the adduct 5a was formed in a
5:95 exo/endo ratio.
The [AlCl3 + 2THF]-catalyzed protocol was then extended
to the cycloadditions of 1c-l with isoprene (2) (Table 2).10
The results were in all cases excellent, and the polymerization
of the diene was always avoided. The regiochemistry of the
reactions was exclusively para, except in the case of
crotonaldehyde (1h), which was converted to adduct 3h in
a 4:1 para/meta ratio.
The reaction of 1k with 2 was also performed on a 50
mmol scale, and similarly, to the 1.0 mmol scale, product
3k was isolated in 93% yield. The reaction was exothermic,
and a careful control of temperature (ice bath) together with
the use of a mechanical stirrer was necessary for achieving
the best results.
To understand the precise role of THF, further studies are
necessary. We hypothesize that [AlCl3 + 2THF] possesses
a lower acidic character compared to AlCl3, being still able
to activate the dienophile via oxygen complexation but not
to react with the diene and to induce the polymerization.
The use of THF as a solvent, obviously preventing the
complexation, depresses both polymerization and cycload-
dition.
In conclusion, in the reactions of 1a-l with 2, 4, and 5,
we have shown that the use of SFC and [AlCl3 + 2THF]
allowed the corresponding cycloadducts to be isolated in high
yields. It is noteworthy that by this approach the diene’s
polymerization is avoided, allowing equimolar amounts of
reagents to be used. The combination of SFC and an adequate
catalyst is a promising approach for improving both the
chemical and the environmental efficiency of the Diels-
Alder reaction.
a Isolated yield. b With 1 mol % of catalyst. c With 2 equiv of isoprene
(2). d Performed at 0 °C. e 4:1 para/meta ratio.
Acknowledgment. The Universita` degli studi di Perugia
and the Ministero dell’Istruzione dell’Universita` e della
Ricerca (MIUR) are thanked for financial support; COFIN
2004; COFINLAB 2001 (CEMIN); FIRB 2001.
(10) Typical procedure for the [AlCl3 + 2THF]-catalyzed reaction of
1a with 2 under SFC: a screw-capped vial equipped with a magnetic stirrer
was charged with 0.05 mmol (0.0066 g) of AlCl3 and 0.10 mmol (0.0072
g) of THF. After 15 min, ethyl acrylate (1a) (1.0 mmol, 0.1002 g) and,
after additional 15 min, isoprene (2) (1.0 mmol, 0.068 g) were added, and
the mixture was left under stirring at 30 °C for 12 h. The final reaction
mixture was purified by silica gel column chromatography (EtOAc/
petroleum ether, 5/95 gradient), and cycloadduct 3a was isolated in 92%
yield (0.154 g).
Supporting Information Available: General experimen-
tal procedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL060569Q
Org. Lett., Vol. 8, No. 12, 2006
2489