Rate accelerations of 1,3-dipolar cycloaddition reactions in ionic liquids

Article abstract of DOI:10.1016/S0040-4039(00)01237-5

The 1,3-dipolar cycloaddition reactions between imidate 1 derived from diethyl aminomalonate and 2-ethoxybenzaldehyde 2 as dipolarophile has been investigated in various air and moisture stable ionic liquids. Significant rate enhancements and improved yie

Full text of DOI:10.1016/S0040-4039(00)01237-5

Tetrahedron Letters 41 (2000) 7351±7355
Rate accelerations of 1,3-dipolar cycloaddition reactions in
ionic liquids
Joan Fraga Dubreuil and Jean Pierre Bazureau*
Á Á Â
Synthese & Electrosynthese Organiques 3, UMR 6510, Universite de Rennes 1, Bat. 10A, Campus de Beaulieu,
Avenue du General Leclerc, F-35042 Rennes, France
Ã
 Â
Received 30 June 2000; accepted 21 July 2000
Abstract
The 1,3-dipolar cycloaddition reactions between imidate 1 derived from diethyl aminomalonate and
2-ethoxybenzaldehyde 2 as dipolarophile has been investigated in various air and moisture stable ionic
liquids. Signi®cant rate enhancements and improved yields at 70ꢀC have been observed with [emim][BF4]
and [emim][NfO] ionic liquids. The reactivity of dipolarophiles covalently grafted on the ionic liquids were
also evaluated. # 2000 Elsevier Science Ltd. All rights reserved.
Room temperature ionic liquids1 are a new class of solvents that are entirely constituted of
ions. These solvents possess a number of interesting properties, especially their lack of vapour
pressure, a wide accessible temperature range with lack of ¯ammability and ease of reuse. Room
temperature ionic liquids are attracting increasing interest as environmentally benign reaction
media and have been found to be excellent solvents for a number of purposes such as Friedel±Crafts
reactions,2 arene hydrogenation,3 dimerizations4 of alkenes, allylation of aldehydes,5 Heck reactions6
and Diels±Alder reactions.7 Recent studies on Diels±Alder reactions in non-aqueous solvents show
strong selectivities which were also associated with considerable acceleration of the process.8
One of the continuing aims of our laboratory is to develop new synthetic routes to ®ve-membered
heterocycles by [3+2] reactions using solvent-free conditions,9 eventually assisted by focused
microwave irradiation.10 Our interest was to explore the ionic liquid methodology in 1,3-dipolar
cycloaddition reactions. Here, we have examined reactions of imidate11 1 derived from diethyl
aminomalonate with 2-ethoxybenzaldehyde 2 as dipolarophile at 70ꢀC (Scheme 1). For this study,
the air stable ionic liquids employed were 1-ethyl-3-methylimidazolium tetra¯uoroborate12a,b
([emim][BF4]), 1-ethyl-3-methylimidazolium hexa¯uorophosphate12c ([emim][PF6]), 1-ethyl-3-
methylimidazolium nona¯uoro 1-butanesulfonate12d ([emim][NfO]) and the novel 3-(5-carboxy-
* Corresponding author. Fax+33 0299286374; e-mail: jean-pierre.bazureau@univ-rennes1.fr
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01237-5

7352
pentyl)-1-methylimidazolium tetra¯uoroborate13 ([capemim][BF4]) which was easily prepared in
two steps using standard procedures (Scheme 2).
Scheme 1.
Scheme 2. Synthesis of [capemim][BF4]. (i) Br(CH2)5CO2H 1 equiv.; 70ꢀC, 4 h. (ii) NH4BF4 2.5 equiv.; dry MeCN,
60ꢀC, 18 h
In a typical reaction, imidate 1 (1 equiv.) and dipolarophile 2 (1 equiv.) were added to the ionic
liquid directly (0.1±1 equiv.). Two phases were formed at room temperature. At 70ꢀC, the mixture
became homogeneous and was stirred vigorously during the appropriate reaction time
1
(monitored by H NMR). Then, the reaction mixture was allowed to cool, the organic layer was
separated and the cycloadduct 3 could be extracted from the ionic liquid with diethyl ether or
ethyl acetate to leave the pure ionic liquid which may be reused.
Table 1 shows the results of a number of 1,3-dipolar cycloadditions in ionic liquids under
various reactions conditions. Reaction rates had to be calculated on the disappearence of imidate
Table 1
Results of the 1,3-dipolar cycloaddition reactions of imidate 1 with 2 in ionic liquids at 70ꢀC in an oil bath or under
focused microwave irradiations (mo)

7353
1
1 and were determined by H NMR. All reactions exhibited pronounced rate accelerations and
good yields were obtained for isolated products 3 with [emim][PF6] (entry 5) and [emim][NfO]
(entry 6). However, it should be noted that the reaction rate in an ionic liquid is dependent upon
the ionic liquid chosen and in this case, [emim][NfO] gives a lower rate enhancement (entry 6)
than the [emim][BF4] and [emim][PF6] ionic liquids (entries 4 and 5). The addition of 5% of
glacial acetic acid as Bronsted catalyst14 in the ionic liquid (entry 9) increases the reaction rate.
Association of focused microwave irradiations15 with glacial acetic acid in [emim][BF4] (entry 10)
is suitable for increasing the reaction rate and the yield of isolated cycloadduct 3. With
[capemim][BF4] (entry 11), we have observed the same rate accelerations but the yield of 3 after
extraction from the crude reaction mixture is moderate16 (3: 51% yield). According to the
pronounced rate enhancement observed previously, it was decided to investigate the reactivity of
benzaldehyde bound to the ionic liquid. The synthesis of the corresponding ionic liquid dipolarophiles
7(a,b) (X=BF4) and 7a0 (X=NfO) is shown in Scheme 3. The aldehydes 5(a,b) were prepared by
a coupling reaction of the sodium salt of 2-hydroxybenzaldehyde17 4a or 3-hydroxybenzaldehyde
4b with 2 equiv. of 1,2-dibromoethane. Next, reaction of methyl imidazole with 5a or 5b at re¯ux
results in the quantitative formation of the corresponding N(1)-alkyl-3-methylimidazolium
bromides 6(a,b). The imidazolium bromides 6(a,b) were readily isolated as pale yellow solids by
repeated washings of the residue with ether (94% yield). Subsequent anion methathesis with
NH4BF4 (2.5 equiv.) or C4F9SO3K (1.5 equiv.) in deionized water followed by extraction with
CH2Cl2 and vacuum evaporation leads to the desired ionic liquid dipolarophiles 7a, 7a0 and 7b.
1
Their purity has been established by acquisition of clean H and 13C NMR as well as by FAB-
MS. The meta ionic liquid 7b remains liquid for weeks, the ortho compounds 7a and 7a0 slowly
glassify at room temperature and are reliqui®ed by mild heating (7a at 56ꢀC and 7a0 at 48ꢀC). The
three organic ionic liquids appear to be stable at room temperature for several weeks.
Scheme 3. (i) (CH2Br)2 2 equiv., NaOH 1.2 equiv., Á, 48 h. (ii) for 6a: TCE, Á, 72 h; for 6b: 80ꢀC, 15 h. (iii) for 7a and
7b: NH4BF4 2.5 equiv., H2O, 60ꢀC, 18 h; for 7a0: nC4F9SO3K 1.5 equiv., H2O, 70ꢀC, 18 h
In order to de®ne the ability of ionic liquid dipolarophiles 7a, 7a0 and 7b for cycloaddition
reactions, we have examined the reactivity of imidate 1 in the same reactions conditions (at 70ꢀC
in oil bath) with a ratio of 1/7:1/1. The results summarized in Table 2 show that reaction of 7a
with imidate 1 at 70ꢀC is not accomplished after a reaction time of 1.5 h (entry 1); the crude
reaction mixture (which contains 8a, unreacted products 7a and 1 together with by product due
to partial hydrolysis of imidate16 1) becomes a soft yellow solid which changes to a gelatinous
state at 100±120ꢀC before becoming fully liquid at 130ꢀC to force the reaction to completion.

7354
With the same experimental conditions, reactions of 1 with 7a0 (entry 2) and 7b (entry 3) are
®nished over a period of 6±7 h; the respective crude reaction mixture appears as a yellowish wax.
It is noteworthy that the reaction of imidate 1 with ionic liquid dipolarophile 7a0 ortho (Table 2,
entry 2: 6.5 h) is more rapid than reaction of 1 with 2-ethoxybenzaldehyde 2 (Table 1, entry 6: 7.5 h)
in [emim][NfO] ionic liquid. This acceleration observed with 7a0 ortho is probably due to the
intramolecular interaction between the CHO group of dipolarophile and the polar 3-methylimi-
dazolium moiety.
Table 2
Results of 1,3-dipolar cycloadditions obtained at 70ꢀC in an oil bath with 2-hydroxy- and 3-hydroxybenzaldehydes
covalently grafted on the ionic liquids (7a, 7a0 and 7b)
In summary, the room temperature ionic liquids [emim][BF4], [emim][PF6] and [emim][NfO]
give signi®cant rate accelerations and good isolated cycloadduct yields when compared to
solvent-free cycloaddition reaction conditions. However, the factors that a€ect this improvement
are at present not fully understood. They are potentially useful solvents particularly for moisture
sensitive reagents, because cycloadducts can be isolated simply by extraction from the crude
reaction mixture and the ionic liquid may be reused. Further studies of possible applications of
dipolarophiles appended to the ionic liquid are also being actively pursued. The results of these
and related studies will be reported in due course.
Acknowledgements
The authors thank Merck Eurolab (Fr) for the generous gift of the focused microwave oven
(Synthewave 402). One of us (J.F.-D.) wishes to thank the 'Ministere de la Recherche et de
l'Enseignement Superieur' for a research fellowship. The authors thank also Professor Jack
Hamelin for fruitful discussions.
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1
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