Grafted ionic liquid-phase-supported synthesis of small organic molecules

Article abstract of DOI:10.1016/S0040-4039(01)01190-X

The preparation and applications in the Knoevenagel and 1,3-dipolar cycloaddition reactions of new grafted soluble liquid phases derived from imidazolium ionic liquids are described. Good yields and high regioselectivity are the features observed with these unconventional liquid phases.

Full text of DOI:10.1016/S0040-4039(01)01190-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6097–6100
Grafted ionic liquid-phase-supported synthesis of
small organic molecules
Joan Fraga-Dubreuil and Jean Pierre Bazureau*
Universite´ Rennes 1, Institut de Chimie, Synthe`se & Electrosynthe`se Organiques 3, UMR 6510, Baˆt. 10A, Campus de Beaulieu,
Avenue du Ge´ne´ral Leclerc, CS 74205, 35042 Rennes Cedex, France
Received 8 June 2001; accepted 29 June 2001
Abstract—The preparation and applications in the Knoevenagel and 1,3-dipolar cycloaddition reactions of new grafted soluble
liquid phases derived from imidazolium ionic liquids are described. Good yields and high regioselectivity are the features observed
with these unconventional liquid phases. © 2001 Elsevier Science Ltd. All rights reserved.
Molecular diversity based on combinatorial organic
synthesis1 is now being used for rapid lead generation
in both drug discovery and the development of biologi-
cally active compounds with potential therapeutic
value. This demand for large numbers of new com-
pounds has in turn, caused chemists to look for ways to
simplify, expedite, and automate the process of small
organic molecule synthesis. Synthetic approaches that
utilise solid phases exhibits several shortcomings owing
to the nature of heterogeneous reaction conditions.2
Reaction kinetics can be non-linear, slow reactions and
degradation of the polymer support after long reaction
time were mentioned. The transfer of traditional solid-
phase synthesis is often complicated. The soluble
polymers3 such as poly(ethylene)glycol (PEG),
poly(styrenes), polyethylenes couple the advantages of
homogeneous solution chemistry (reaction kinetics, lack
of diffusion phenomena) with those of solid-phase
methods (the ability to use an excess of reagents to
drive a reaction to completion, ease of analysis and
including ease of product isolation). The fact that they
can, in certain cases, be recycled for repeated use is also
interesting.
tion. By modification of the cation and anion, their
properties can be turned in many ways. There are
basically three modes of operation: use of the ionic
liquid as a co-solvent, as a pure solvent or in a biphasic
system.6
In this paper, we report our results about the first
application of ILs for liquid-phase synthesis into the
field of supported reagent. We have chosen the ILs as
liquid phase because: (1) they are soluble in a wide
range of both inorganic and organic materials, (2) they
are immiscible with a number of organic solvents and
provide a non-aqueous alternative for two-phase sys-
tems, and (3) ionic liquid phases are simple to prepare
and are potentially compatible with a broad spectrum
of reactions.7
Usual polymers for liquid-phase synthesis must also
provide a reasonable compromise between loading
capacity and solubilising power. With ILs as liquid
phases, the loading capacity was easily evaluated using
1H or 13C spectroscopy and after cleavage the starting
IL phase was recovered and reused for a further cycle.
Previous work4 from our group has demonstrated that
room-temperature ionic liquids (IL) gave significant
rate enhancements and improved yields in solvent-free
1,3-dipolar cycloaddition when the dipolarophile was
covalently grafted on the ionic liquid. ILs5 have gained
increasing attention for performing all types of reac-
As a suitable model reaction for ionic liquid-phase-sup-
ported organic synthesis, we have chosen to use ben-
zaldehyde bound to the ionic liquid moiety. The
synthesis of the corresponding grafted ionic liquid
phases 7(a–d) is shown in Scheme 1. For the prepara-
tion of the starting 4-(2-formylphenoxy)butyric acid8 3,
salicylaldehyde 1 was reacted in a Williamson ether
synthesis with ethyl bromobutyrate (EBB) to give ester
2 in 97% yield followed by saponification with KOH in
refluxing MeOH (3: 92% yield).
* Corresponding author. Fax: +(33) 02 99 28 63 74; e-mail:
jean-pierre.bazureau@univ-rennes1.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01190-X

6098
J. Fraga-Dubreuil, J. P. Bazureau / Tetrahedron Letters 42 (2001) 6097–6100
iii
OH
N
N
N
N
, X
OHC
98%
Route A
97%
v
4
O
5 : X = Cl
iv
R1
N
O
3
N
6 : X = BF4 (85%)
O
, X
7(a-d)
i
O
O
OR
97%
OH
O
7a : R1 = Me, X = BF4 (97%)
7b : R1 = Et, X = BF4 (97%)
7c : R1 = Bu, X = BF4 (97%)
7d : R1 = Bu, X = PF6 (98%)
O
1
Route B
x
2 : R = Et
3 : R = H (92%)
ii
O
O
O
O
ix
R1
N
O
N
N
O
N
O
R1I
, I
O
11 (81%)
12(a-c)
12a : R1 = Me (99%), 12b : R1 = Et (92%),
12c : R1 = Bu (97%)
3
viii
vi
62%
vii
H
OH
N
N
O
N
N
N
N
N
63%
N
H
8
9
10
Scheme 1. Reagents and conditions: (i) EBB, K2CO3 (2 equiv.), MeCN, reflux, 24 h; (ii) KOH 2N, MeOH, reflux, 1.5 h, HCl 5N;
(iii) chloroethanol (1 equiv.), 80°C, N2, 96 h; (iv) NH4BF4 (3 equiv.), MeCN, 60°C, 20 h; (v) DCC (1 equiv.), DMAP (5%),
MeCN, rt, 18 h; (vi) chloroethanol (1 equiv.), EtONa (1.1 equiv.), EtOH, reflux, 12 h.; (vii) DCC (1 equiv.), CuCl (0.1 equiv.),
70°C, 24 h; (viii) 3 (1 equiv.), MeCN, reflux, 20 h, satd NaHCO3; (ix) for 12a: MeI (1.5 equiv.), DCM, reflux, 72 h; for 12b: EtI
(1.5 equiv.), CHCl3, reflux, 96 h; for 12c: BuI (1 equiv.), MeCN, reflux, 72 h; (x) for 7(a–c): NH4BF4 (2 equiv.), MeCN, reflux,
48 h; for 7d: KPF6 (1.1 equiv.), THF, rt, 24 h.
Two synthetic strategies were developed for the prepa-
ration of the ionic liquid phases 7(a–d). In the direct
route A, the novel 1-(2-hydroxyethyl)-3-methylimida-
zolium tetrafluoroborate ([hydemim][BF4]) 6 was easily
prepared in two steps using standard procedures (83%
yield). Then esterification of 3 (1.01 equiv.) with the IL
6 in dry MeCN in the presence of dicyclohexyl-
carbodiimide9 (DCC) produced the new ionic liquid
phase 7a in more than 97% yield as pale yellow oil after
repeated washings of the crude residue with benzene.
The conversion was almost quantitative as judged by
tion of the solvent. At room temperature the ILPs 7 are
viscous oils and became fully liquid at 60°C without
decomposition.12
In order to define the ability of the ILPs 7a13 in
liquid-phase combinatorial synthesis, we have checked
the reactivity of the formyl group covalently grafted on
the IL phase for Knoevenagel reactions14 and dipolar
cycloadditions. As shown in Scheme 2, we obtained
successfully catalysed (2% of piperidine) Knoevenagel
reactions with malonate derivatives 13 (1 equiv.) using
solvent-free conditions associated with focused
microwave irradiations15 (mv: Synthewave® 402 oven16)
after a short reaction time (15–60 min) at 80°C. Follow-
ing AcOEt or Et2O washings of the IL phase, the
bound products 14(a–c) were subjected to a very
efficient cleavage from the IL phase with NaOMe in
methanol.17 Reaction progress was conveniently moni-
1
acquisition of clean H and 13C NMR as well as by
FAB-MS. In route B, we directed our efforts toward a
simple and general route to imidazolium iodides 12
with various lipophilic side chains of the cation. The
available N,N%-dicyclohexyl isourea10 10 (63% yield)
from 2-imidazol-1-yl ethanol11 9 (62% yield from 8)
reacted with 3 in refluxed MeCN for 20 h. After
repeated washings with saturated NaHCO3, ester 11
was obtained in 81% yield and undergoes quantitative
quaternisation with alkyl iodides (12(a–c): 92–99%).
Subsequent anion metathesis of iodide salts 12(a–c)
with NH4BF4 (2 equiv.) or KPF6 (1.1 equiv.) respec-
tively in MeCN (60°C, 2 days) and in THF (25°C, 24 h)
leads to the desired grafted ionic liquid phases 7(a–d).
These ionic liquid phases (ILPs) 7 are isolated in high
yield (ꢀ98%) as straw-coloured liquids after filtration
to remove NH4I or KI followed by vacuum evapora-
1
tored by H and 13C NMR spectroscopy. After removal
of solvent in vacuo, the expected compounds 15(a–c)
were extracted with CH2Cl2 in 87% yield without the
need for silica gel chromatography (Table 1) and,
finally, it was possible to reuse the insoluble
[hydemim][BF4] 6 in another cycle of synthesis.18
By utilising this IL-phase methodology, reaction of 7a
with various alkylamines 16 (1 equiv.) gave the desired
bound aldimines 17(a–c) in short reaction times (20

J. Fraga-Dubreuil, J. P. Bazureau / Tetrahedron Letters 42 (2001) 6097–6100
6099
Scheme 2. Reagents and reaction conditions: (i) 13 (1 equiv.), piperidine (2%), mv, 80°C; (ii) MeONa (0.1 equiv.), MeOH, rt, 18
h; (iii) 16 (1 equiv.), mv, 80°C, 20 min; (iv) 18 (1 equiv.), 70°C, 15 h.
min). The successful regioselective addition of amines
onto the IL-phase 7a will allow diversity introduction
at this step, i.e. R=iPr (17a, 93%), nPr (17b, 95%), tBu
(17c, 84%). Next, the IL-phase dipolarophile 17b was
submitted to a regioselective 1,3-dipolar cycloaddition19
reaction with the imidate 18 derived from dimethyl
aminomalonate (1 equiv.). Finally, treatment of bound
cycloadduct 19b with 10% NaOMe in MeOH resulted
also in a practical cleavage from the Il phase to provide
only the diethyl 2-imidazoline-4,4-dicarboxylate 20b in
Table 1. Compounds 14 and 15 generated via Scheme 2
Compound
EWG1
EWG2
Reaction time Yield (%)c
14a
14b
14c
14d
14e
15a
15b
15c
CO2Me CN
CO2Me CO2Me
15 mina
1 ha
98
98
98
98
98
87
87
87
CO2Et
CN
CO2Et
CN
1 ha
15 mina
2 ha
COMe
COMe
CO2Me CN
18 hb
CO2Me CO2Me 18 hb
18 hb
1
84% yield and the structure was confirmed by H, 13C
CN
CN
NMR and FAB-MS.
a The reaction was monitored by 1H NMR spectroscopy in CDCl3 as
solvent with TMS as internal reference.
In summary, we have shown that benzaldehyde bound
to IL can be readily prepared and used in Knoevenagel
reactions and 1,3-dipolar cycloadditions using solvent-
free conditions assisted by focused microwave irradia-
b The reaction was considered complete when no starting compound
13 was detected by TLC.
c Yields are based on the conversion of 13 to 14, 14 to 15 and are
isolated yields.

6100
J. Fraga-Dubreuil, J. P. Bazureau / Tetrahedron Letters 42 (2001) 6097–6100
tions. Product isolation is routine and the reactions are
high yielding. The use of this novel IL phase in liquid-
phase organic synthesis (LPOS) offers considerable
advantages because the side product is removed by
simple extraction and washings from the cleaved IL
phase, so no chromatography is necessary. In contrast
to the various restrictions of reaction development in
solid-phase synthesis, IL phases allow standard analyti-
cal methods (NMR, TLC) to monitor reaction pro-
gress. This work has highlighted a novel soluble-phase
approach to LPOS. Perhaps one of the exciting features
of the IL phases is their generality, with potential
applications to many other chemistries. Finally the
IL-phase methodology should be compatible with high-
throughput organic synthesis and automation technol-
ogy. We are currently exploring the scope and the
potential of microwave assisted liquid-phase synthesis20
by extending this approach to other IL-phase
transformations.
12. Ngo, H. L.; LeCompte, K.; Hargens, L.; McEwen, A. B.
Thermochem. Acta 2000, 357–358, 97.
13. Typical procedure for the preparation of 1-{2-[4-(2-
formylphenoxy)butyryloxy]ethyl}-3-methyl-3H-imidazol-
1-ium tetrafluoroborate (7a) (route A): To a mixture of
dicyclohexylcarbodiimide (2.97 g, 14.42 mmol) and
dimethylaminopyridine 5% (88 mg, 0.7 mmol) in dry
acetonitrile
[hydemim][BF4] 6 (3.08 g, 14.42 mmol) in one portion,
then 4-(2-formylphenoxy)butyric acid (3 g, 14.42
(75
ml)
were
added
successively
3
mmol). After vigorous stirring at rt for 18 h, the insoluble
N,N%-dicyclohexylurea was eliminated by filtration. The
filtrate was concentrated under reduced pressure and the
resulting crude reaction mixture was washed three times
with benzene (20 ml). Removal of the solvent in vacuo
lead to a pale yellow viscous oil in 97% yield. The ionic
liquid phase 7a was stored under an inert atmosphere at
4°C. 1H NMR lH [(CD3)2CO, 300 MHz] 2.15 (quint.,
2H), 2.66 (t, 2H), 4.02 (s, 1H), 4.20 (t, 2H), 4.52 (t, 2H),
4.66 (t, 2H), 7.06 (t, 1H), 7.20 (d, 1H), 7.63 (ddd, 1H),
7.67 (t, 1H), 7.73 (dd, 1H), 7.78 (t, 1H), 9.02 (s, 1H),
10.44 (s, 1H); 13C NMR lC [(CD3)2CO, 75 MHz] 24.9,
30.8, 36.6, 49.5, 63.1, 68.3, 114.0, 121.4, 123.9, 124.7,
125.7, 128.4, 137.0, 138.1, 162.1, 173.2, 189.8; HRMS,
m/z: 317.1497 found (calcd for C17H21N2O4, M+ requires:
317.1501)
Acknowledgements
J. Fraga-Dubreuil wishes to thank the Ministe`re de la
Recherche et de l’Enseignement Supe´rieur for
a
research fellowship. We also thank Professor Jack
Hamelin for fruitful discussions.
14. (a) Che´rouvrier, J. R.; Boissel, J.; Carreaux, F.;
Bazureau, J. P. Green Chem. 2001, in press; (b) Vanelle,
P.; Meuche, J.; Maldonado, J.; Crozet, M. P.; Delmas,
F.; Timon-David, P. Eur. J. Org. Chem. 2000, 157; (c)
Bourmendjel, A.; Nuzillard, J. M.; Massiot, G. Tetra-
hedron Lett. 1999, 40, 9033; (d) Chamontin, K.; Lokskin,
V.; Rossollin, V.; Samat, A.; Guglielmetti, R. Tetra-
hedron 1999, 55, 5821; (e) Michaud, D.; Ayoubi, S. A.;
Dozias, M. J.; Toupet, L.; Texier-Boullet, F.; Hamelin, J.
Chem. Commun. 1997, 1613.
15. (a) Varma, R. S. Green Chem. 1999, 1, 43; (b) Loupy, A.;
Petit, A.; Hamelin, J.; Texier-Boullet, F.; Jacquault, P.;
Mathe´, D. Synthesis 1998, 1213; (c) Caddick, S. Tetra-
hedron 1995, 51, 10403.
16. Commarmot, R.; Didenot, R.; Gardais, J. F. Fr.
Demande 25 560 529, 1985; Chem. Abstr. 1986, 105,
17442.
17. (a) Chi, Y. C.; Sun, C. M. Synthesis 2000, 591; (b)
Shuttleworth, S. J.; Allin, S. M.; Sharma, P. K. Synthesis
2000, 1217; (c) Shuttleworth, S. J.; Allin, S. M.; Wilson,
R. D.; Nasturica, D. Synthesis 2000, 1035.
18. Before using [hydemim][BF4] 6 in the second run, the
IL-phase 6 was washed twice with methylene chloride (15
ml). After addition of acetone and filtration, the filtrate
was concentrated in vacuo. Then, the grafted IL-phase 7a
was synthesised also in high yield (97%) with the same
reaction time (18 h) from [hydemim][BF4]) 6 according to
the experimental procedure describe in Ref. 13.
References
1. Ley, S. V.; Baxendale, J. R.; Bream, R. N.; Jackson, P.
S.; Leach, A. G.; Longbottom, D. A.; Nesi, M.; Scott, J.
S.; Storer, R. I.; Taylor, S. J. J. Chem. Soc., Perkin Trans.
1 2000, 23, 3815 and references cited therein.
2. Yan, B. Acc. Chem. Res. 1998, 31, 621 and references
cited therein.
3. (a) Toy, P. H.; Janda, K. D. Acc. Chem. Res. 2000, 33,
546; (b) Wentworth, Jr., P.; Janda, K. D. Chem. Com-
mun. 1999, 1917; (c) Gravert, D. J.; Janda, K. D. Chem.
Rev. 1997, 97, 489.
4. Fraga-Dubreuil, J.; Bazureau, J. P. Tetrahedron Lett.
2000, 41, 7351.
5. (a) Wasserscheid, P.; Keim, W. Angew. Chem., Int. Ed.
2000, 39, 3772; (b) Hagiwara, R.; Ito, Y. J. Fluorine
Chem. 2000, 105, 221; (c) Welton, T. Chem. Rev. 1999,
99, 2071; (d) Seddon, K. R. J. Chem. Tech. Biotechnol.
1997, 38, 351; (e) Seddon, K. R. Kinet. Catal. Engl.
Transl. 1996, 37, 693.
6. Olivier, H. J. Mol. Catal. A 1999, 146, 285.
7. (a) Sundermeyer, W. Angew. Chem. 1965, 77, 241; Angew.
Chem., Int. Ed. Engl. 1965, 4, 222; (b) Sundermeyer, W.
Chem. Unserer Z. 1967, 1, 150; (c) Volkov, S. V. Chem.
Soc. Rev. 1990, 19, 21.
19. (a) de La Hoz, A.; Diaz-Ortis, A.; Morenos, A.; Langa,
F. Eur. J. Org. Chem. 2000, 3659; (b) Fraga-Dubreuil, J.;
Cherouvrier, J. R.; Bazureau, J. P. Green Chem. 2000, 2,
226.
8. Benson, D. R.; Valentekovich, R.; Tam, S. W.;
Diederich, F. Helv. Chim. Acta 1993, 76, 2034.
9. Mathias, L. J. Synthesis 1979, 561.
10. Vowinkel, E.; Wolff, C. Chem. Ber. 1974, 107, 496.
11. Giesemann, H. J. Prakt. Chem. 1957, 4, 169.
20. Stadler, A.; Kappe, C. O. Eur. J. Org. Chem. 2001, 919.
.