Endo selective Diels-Alder reactions of furan in ionic liquids

Article abstract of DOI:10.1055/s-2002-34868

Diels-Alder reactions of the heteroaromatic diene furan proceed with enhanced isolated yields and reversal of endolexo selectivity (2:1 endo vs exo) in the ionic liquids [bmim]BF₄ and [bmim]PF₆ compared to conventional methods. The p

Full text of DOI:10.1055/s-2002-34868

LETTER
1815
Endo Selective Diels–Alder Reactions of Furan in Ionic Liquids
Endo
S
el
v
e
ctive Diels–
a
A
lder Reac
n
tions of Furan in
IH
onic Liquids emeon,a Carolyn DeAmicis,a Hilary Jenkins,a Peter Scammells,b Robert D. Singer*a
a
Department of Chemistry, Saint Mary’s University, Halifax, B3H 3C3 Canada
Fax +1(902)4205261; E-mail: robert.singer@stmarys.ca
b
Department of Medicinal Chemistry, Victorian College of Pharmacy, Monash University, Victoria, 3052 Australia
Received 17 April 2002
applications in Diels–Alder chemistry.7 However, the
range of dienes utilized in ionic liquid solvents remains
limited and typically involves such dienes as cyclopenta-
diene. Some of the highest endo/exo ratios have been ob-
Abstract: Diels–Alder reactions of the heteroaromatic diene furan
proceed with enhanced isolated yields and reversal of endo/exo se-
lectivity (2:1 endo vs exo) in the ionic liquids [bmim]BF4 and
[bmim]PF6 compared to conventional methods. The potential utility
of ionic liquids as solvents in Diels–Alder reactions of thiophene tained for the reaction of methylacrylate and
cyclopentadiene in chloroaluminate based ionic liquids.7c
and pyrrole derivatives has also been demonstrated.
Use of these Lewis acidic ionic liquids precludes the use
of furan and other heteroaromatic dienes due to their lack
of stability in the presence of common Lewis acids. The
propensity of Diels–Alder adducts derived from furan to
undergo retro-Diels–Alder reactions, especially upon
heating, prohibit the use of ionic liquids that melt at or
above room temperature as solvents for these reactions.
Hence, room temperature ionic liquids such as 1-butyl-
3-methylimidazolium tetrafluoroborate, [bmim]BF4, (mp
–81 °C)8 and 1-butyl-3-methylimidazolium hexafluoro-
phosphate, [bmim]PF6 (mp 4 °C)8 were considered viable
candidates for solvents to be used in Diels–Alder reac-
tions involving furan and other heteroaromatic dienes.
Key words: Diels–Alder reactions, heterocycles, solvent effects,
furans, pyrroles
In the course of our investigations towards the total syn-
thesis of adenosine receptor agonists containing an endo
5-substituted 7-oxabicyco[2.2.1]hept-2-ene moiety we
encountered unfavourable endo/exo selectivity using con-
ventional Diels–Alder methodologies in the preparation
of 7-oxabicyco[2.2.1]hept-2-ene precursors (Scheme 1).1
Under most conventional conditions the exo isomer of 5-
substituted 7-oxabicyco[2.2.1]hept-2-ene systems is the
major isomer.2 The use of furan as a diene in Diels–Alder
reactions is also plagued by several other difficulties.
Furan is Lewis acid sensitive and, when reacted with
dienophiles, the resulting products readily undergo retro-
Diels–Alder reactions to reform starting materials or are
cleaved to form 2-substituted furans. Literature examples
of Diels–Alder reactions of furan include those with very
long reaction times,3 ZnI2 at 40 °C in a sealed tube,2 high
pressure (20 000 atm),4 and the use of zeolites.5 Attempts
to improve yields of these reactions by using excess diene
lead to by-product formation and hence purification of
sensitive cycloadducts is further complicated.
We report herein the use of the air and moisture stable ion-
ic liquids [bmim]BF4 and [bmim]PF6 as solvents for Di-
els–Alder reactions of furan with dienophiles of specific
interest towards the total synthesis of potential adenosine
agonists. We have shown that these solvents also have po-
tential for use in Diels–Alder reactions of thiophene and t-
BOC-pyrrole dienes. These reactions have been shown to
proceed with increased isolated yields of adducts, and in
the case of furan reacting with methyl acrylate, with endo
selectivity. This endo selectivity is the opposite to that ob-
tained using conventional methods. The extension of ionic
liquid methodology to heteroaromatic dienes in Diels–Al-
der reactions demonstrates how these solvents increasing-
Ionic liquids have been gaining much popularity as sol-
vents in a number of synthetic methodologies6 including
O
O
H
O
O
+
HN
H
OCH3
N
N
COCH3
OH
Endo
N
N
O
HO OH
Scheme 1 Retrosynthetic analysis of potential adenosine receptor agonist
Synlett 2002, No. 11, Print: 29 10 2002.
Art Id.1437-2096,E;2002,0,11,1815,1818,ftx,en;S02202ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

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I. Hemeon et al.
LETTER
ly provide practical alternatives to conventional solvents due to increased solubility of adducts in [bmim]PF6 result-
for synthetic applications.
ing in difficulty in extraction of these products from the
reaction mixtures using common organic solvents (see
typical procedure). Since [bmim]BF4 is readily soluble in
water whereas the Diels–Alder adducts extract into the or-
ganic phase during extraction [bmim]BF4 could be easily
separated from the desired product. However, the hydro-
phobic nature of [bmim]PF6 complicated the separation of
the adducts from the ionic liquid solvent using a simple
organic–aqueous phase extraction.
Typically 1.4 equivalents of the diene was reacted with
the dienophile in the presence of 30 mol% or 100 mol% of
a ZnI2 in [bmim]BF4 or [bmim]PF6. [Bmim]PF6 had been
exhaustively washed with de-ionized water until pH neu-
tral and both [bmim]BF4 and [bmim]PF6 were dried on
high-vac prior to use. With the exception of entries 13 and
15 in Table 1 none of the reactions proceeded without the
inclusion of this mild Lewis acid. Indeed it had been
shown in previous studies that ZnI2 catalyzed the reaction We sought to extend the use of ionic liquids as solvents in
of furan with methyl acrylate.2 Attempts to use stronger the Diels–Alder reactions of other heteroaromatic dienes
Lewis acids such as BF3 OEt2 or chloroaluminate based that pose some of the same difficulties as furan. Hence, we
ionic liquids such as [bmim]Al2Cl7 resulted in the decom- reacted thiophene with dimethylacetylene dicarboxylate,
position of the reactants. All reactions in Table 1 were DMAD, in the presence of 30 mol% of ZnI2 in [bmim]BF4
conducted at room temperature to avoid retro-Diels–Al- at room temperature. This reaction afforded a 44% isolat-
der reactions of the adducts once they had formed. Reac- ed yield of the Diels–Alder adduct upon purification by
tion times were typically 48–72 hours; these were similar column chromatography. This is an improvement over
to those reported elsewhere in the literature for reactions conventional methodology in which typically lower
that gave poorer results under conventional conditions. yields are obtained for this reaction.11 We also reacted t-
Reactions were stopped after no further change in product BOC-pyrrole with DMAD under similar conditions but in
mixtures were observed by gas chromatography with the the absence of ZnI2. Although the isolated yield of the ad-
balance of starting material remaining unreacted.
duct was low (i.e. 23%) this is still comparable to those re-
ported elsewhere for related pyrrole Diels–Alder adducts
formed in an uncatalyzed reaction.12 The crystal structure
of this adduct is shown in Figure 1. This structure con-
firms the assigned structure for this adduct as the ‘mono’
Diels–Alder adduct. It is significant that the adducts ob-
tained for Table 1, entries 14 and 15 did not undergo fur-
ther Diels–Alder reaction with diene present in the system
as they formed.13
In our study it was demonstrated that use of 30 mol% of
ZnI2 afforded a slightly better endo/exo ratio than the use
of a full equivalent of ZnI2 (Table 1, entry 1 vs 2 and 3 vs
4). Use of a full equivalent of ZnI2 seems to have promot-
ed formation of more exo adduct (e.g. both endo and exo
formation are catalyzed in the presence of 1 full equiva-
lent of ZnI2) resulting in an increased isolated yield of ad-
ducts with a slightly decreased selectivity (i.e. entry 1 vs
entry 2). In all cases, the use of ZnI2 to catalyze the reac-
tion in [bmim]BF4 or [bmim]PF6 resulted in a reversal of
the endo/exo ratio as compared to those reactions conduct-
ed under other conditions without ionic liquids.2 Similar
endo selectivity in ionic liquid solvents has been attribut-
ed to the highly ordered hydrogen-bonded nature of ionic
liquids that leads to stabilisation of the more polar endo
activated complex and/or association of reagents in a ‘sol-
vent cavity’ during the rate determining step.7b The use of
a full equivalent of ZnI2 in these reactions served to in-
crease the overall chemical yield of the Diels–Alder ad-
duct isolated from the ionic liquid reaction solutions. It is
noteworthy that Table 1 shows isolated yields that are
much improved over those reported elsewhere and that
when methyl acrylate is the dienophile the endo/exo ratio
favour the formation of the endo adducts rather than the
exo.2,4,5,9 For example, Table 1, entry 1 shows that in
[bmim]BF4 a 67% isolated yield is obtained with a 2.3:1
endo:exo ratio compared to a 55% yield with a 1:2 en-
do:exo ratio under solventless conditions.2 In agreement
with literature reports we obtained exclusively exo ad-
ducts when furan was reacted with maleic anhydride.10
Figure 1 X-Ray crystal structure of 7-(tert-butyl) 2,3-dimethyl-7-
azabicyclo[2.2.1]hepta-2,5-diene-2,3,7-tricarboxylate; adduct from
Table 1, entry 15
The use of the ionic liquids [bmim]BF4 and [bmim]PF6 in
the Diels–Alder reactions of furan, thiophene, and t-BOC-
pyrrole with simple dienophiles such as methylacrylate,
maleic anhydride, and DMAD affords higher isolated
yields of adducts than those methods previously reported.
Interestingly, these ionic liquid systems induce a reversal
of the endo/exo selectivity in the reaction of furan with
methylacrylate. [Bmim]BF4 is a superior solvent to
[bmim]PF6 since it allows products to be more easily iso-
Use of freshly prepared, pH neutral, and dried [bmim]PF6
generally resulted in a decrease in the isolated yields of
adducts as compared to those reactions conducted in dry
[bmim]BF4. However, they were still higher yields than
those obtained under conventional means. This may be
Synlett 2002, No. 11, 1815–1818 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Endo Selective Diels–Alder Reactions of Furan in Ionic Liquids
1817
Table 1 Diels–Alder Reactions of Heteroaromatic Dienes in [bmim]BF4 and [bmim]PF6
Entry
1
Ionic Liquid
[bmim]BF4
Diene
Dienophile
ZnI2
(mol%)
Yield
Literature yield
(endo/exo)
(endo/exo)a,b
30
100
30
67% (2.3:1)
75% (1.8:1)
42% (2.3:1)
73% (1.4:1)
55% (1:2)2
O
O
OCH3
2
3
4
[bmim]BF4
[bmim]PF6
[bmim]PF6
–
–
O
O
O
O
OCH3
O
OCH3
100
–
O
OCH3
c
5
6
[bmim]BF4
[bmim]BF4
[bmim]PF6
[bmim]PF6
[bmim]BF4
[bmim]BF4
[bmim]PF6
[bmim]PF6
[bmim]BF4
30
100
30
79% (0:1)
73% (0:1)
38% (0:1)
52% (0:1)
32%
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
–
O
O
7
–
O
O
8
100
30
–
O
O
9
20%13
H3CO2C
H3CO2C
H3CO2C
H3CO2C
CO2CH3
CO2CH3
CO2CH3
CO2CH3
10
11
12
13
100
30
22%
–
–
19%
100
0
4%
–
c
21%
O
Cl
d
14
15
[bmim]BF4
[bmim]BF4
30
0
44%
23%
H3CO2C
H3CO2C
CO2CH3
CO2CH3
S
40%e
O
C
O
N
a All yields are isolated yields.
b Structures of adducts confirmed by 1H NMR, 13C NMR, and MS; endo/exo ratios determined by 1H NMR.
c Product has been synthesized but no yields reported (ref.10 for entry 5, ref.1 and ref.9 for entry 13).
d Desulfurized product of thiophene and dicyanoacetylene has been reported in 8% yield.11
e 40% yield of trimethyl pyrrole-N,3,4-tricarboxylate (product of methyl pyrrole-N-carboxylate and DMAD which has undergone retro-Diels–
Alder to lose acetylene).14
lated in higher yields. Both ionic liquids allow the use clo[2.2.1]hept-2-enes obtained from these reactions as
of lower reaction temperatures for these Diels–Alder precursors to potential adenosine agonists is under inves-
reactions. The use of the endo enriched 7-oxabicy- tigation.
Synlett 2002, No. 11, 1815–1818 ISSN 0936-5214 © Thieme Stuttgart · New York

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I. Hemeon et al.
LETTER
Typical Procedure
References
[bmim]BF4 (2.0 mL) was heated under vacuum at 60 °C for 2 h in a
25 mL round bottom flask. ZnI2 (0.96 g, 3.0 mmol, weighed in
glove box into oven-dried vial) was added under a stream of N2 and
the mixture was heated under vacuum for a further 2 h. Methyl acry-
late (0.90 mL, 10.0 mmol) was injected after cooling and sealing the
flask with a septum. This stirred for 15 min in a r.t. water bath, after
which time freshly distilled furan (1.02 mL, 14.0 mmol) was inject-
ed. This was stirred for 48 h at r.t., after which time the reaction was
diluted with 100 mL EtOAc. This was washed with 0.1 M Na2S2O3
(1 50 mL) and water (1 50 mL), then dried (MgSO4), filtered,
and concentrated to a yellow oil. The crude product was purified via
flash chromatography using 10:1 hexanes:EtOAc, followed by a 2:1
mixture. The product was isolated as a yellow oil (0.665 g, 4.31
mmol, 67%). 1H NMR indicated an endo:exo ratio of 2:1. 1H NMR:
= 1.59 (dd, H3n endo, exo), 2.06–2.19 (m, 1 H, H3 endo, exo),
2.44 (q, H2 exo), 3.12 (quintet, H2 endo), 3.65 (s, CH3 endo), 3.76
(s, CH3 exo), 5.01–5.19 (m, 2 H, H1 endo, exo, H4 endo, exo), 6.34
(ddd, H5 endo, H6 endo), 6.39 (ddd, H5 exo, H6 exo); 13C NMR:
= 28.4, 28.9, 42.5, 51.6, 52.0, 77.8, 78.6, 78.9, 80.7, 132.4, 134.5,
136.9, 172.5, 174.1; MS (ES+): 154.1.
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Acknowledgement
We would like to acknowledge the Natural Sciences and Enginee-
ring Research Council of Canada (NSERC) and Saint Mary’s Uni-
versity (Senate Research) for funding this research. The Centre for
Chiral and Molecular Technologies at Deakin University, Geelong,
Australia is also thanked for their hospitality during the sabbatical
visit of R.D.S.
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Synlett 2002, No. 11, 1815–1818 ISSN 0936-5214 © Thieme Stuttgart · New York