Base-promoted reactions in ionic liquid solvents. The Knoevenagel and Robinson annulation reactions

Article abstract of DOI:10.1016/S0040-4039(01)01228-X

When used in place of classical organic solvents, ionic liquids offer a new and environmentally benign approach toward solvation in modern synthetic chemistry. Two classical named reactions, the Knoevenagel condensation and Robinson annulation, have been

Full text of DOI:10.1016/S0040-4039(01)01228-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6053–6055
Base-promoted reactions in ionic liquid solvents.
The Knoevenagel and Robinson annulation reactions
Doug W. Morrison,a David C. Forbesa,* and James H. Davis, Jr.a,b,
*
aDepartment of Chemistry, University of South Alabama, Mobile, AL 36688, USA
bCenter for Green Manufacturing, University of Alabama, Tuscaloosa, AL 35487, USA
Received 17 April 2001; accepted 5 July 2001
Abstract—When used in place of classical organic solvents, ionic liquids offer a new and environmentally benign approach toward
solvation in modern synthetic chemistry. Two classical named reactions, the Knoevenagel condensation and Robinson annulation,
have been studied using the ionic liquid 1-hexyl-3-methyl imidazolium hexafluorophosphate, [6-mim]PF6 as solvent. Yields for
each reaction were moderate to excellent. In each system the ionic liquid was successfully recycled for reuse in subsequent reaction
runs, a factor of key importance to the ‘green’ nature of solvation with ionic liquids. © 2001 Published by Elsevier Science Ltd.
With vanishingly small vapor pressures and the capac-
ity to solvate an array of organic and inorganic sub-
strates, ionic liquids are promising substitutes for
volatile organic solvents (VOCs).1 Already these ver-
satile liquids have been used in place of traditional
molecular solvents in a variety of organic reactions, and
recent developments have been ably reviewed.2 Despite
the surging pace of research in the use of ILs as organic
reaction solvents, the preponderance of this research
has centered upon reactions that are metal catalyzed.2
Robinson annulation reactions. Both of these funda-
mentally important synthetic transformations are typi-
cally carried out in a volatile organic solvent.
The model reactions were both conducted in a common
ionic liquid (Fig. 1), 1-hexyl-3-methyl imidazolium hexa-
fluorophosphate, [6-mim]PF6.11 This ionic liquid was
chosen for its ease of preparation as well as its good
balance of desirable physical and chemical properties.
These include thermal stability, relatively low viscosity
and a good capacity for solubilizing organic substrates.
Among organic reaction types that are not metal cata-
lyzed, but which have been achieved in ionic liquids are
the alkylation of phenolic oxygen and the benzoin
condensation.3,4 Both of these reactions are carried out
under basic conditions, yet remain isolated examples of
the genre despite the vast number of organic reactions
that are similarly base-promoted. Given our earlier
success with IL solvation–catalysis of the benzoin con-
densation, we decided to further investigate the use of
ionic liquids in other base-promoted reactions. These
continuing efforts are complimentary to our other,
ongoing work on various aspects of ionic liquids chem-
istry and synthetic methods development.5–10
Both reactions proceed in a straightforward fashion
(Scheme 1), in air and without any rigorous drying of
the ionic liquid.12 In the case of the model Knoevenagel
reaction, glycine was used as the base. The glycine and
the reaction substrates malononitrile and benzaldehyde
dissolved readily in the ionic liquid. After stirring for 22
h at room temperature, the reaction product was
extracted from the ionic liquid phase using an immis-
cible co-solvent, toluene. Significantly, it has been
demonstrated that dissolved organic substrates can be
separated from an ionic liquid system by extraction
with a ‘green’ cosolvent, supercritical CO2.12 The unop-
timized yield of chromatographed product was excellent
(77%), and the ionic liquid was readily re-used for
repeat runs of the reaction. The latter consideration is
of particular significance given that a key rationale for
We report here the successful ‘proof-of-concept’ execu-
tion in ionic liquids of two related reactions, the unify-
ing features of which are their base dependence and the
use in them of substrates with activated methylene
groups. Specifically, these are the Knoevenagel and
* Corresponding authors. Fax: 251 460-7359; e-mail: dforbes@
jaguar1.usouthal.edu; jdavis@jaguar1.usouthal.edu
Figure 1.
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(01)01228-X

6054
D. W. Morrison et al. / Tetrahedron Letters 42 (2001) 6053–6055
Scheme 1.
pursuing studies in ionic liquids is to develop ‘greener’
syntheses through suppressing solvent evaporative loss.
Petroleum Research Fund, administered by the Ameri-
can Chemical Society, the Department of Chemistry and
Research Council at the University of South Alabama for
support of this research. J.H.D., D.C.F. and D.W.M.
wish to thank R. D. Mayton and E. D. Bates of the Davis
group for preparing the ionic liquid used in this study.
Likewise, the Robinson annulation of ethyl acetoacetate
and trans-chalcone was uncomplicated. The reaction
procedure deviates somewhat from that used in the
Knoevenagel reaction in that pulverized NaOH was used
as the base, and the reaction mixture heated to 100°C for
1.5 h. Workup by neutralization of the reaction mixture
with aqueous acid followed by extraction with toluene
then silica gel chromatography gave 6-ethoxycarbonyl-
3,5-diphenyl-2-cyclohexenone in modest (48%) unopti-
mized yield. Again, the ionic liquid could be recycled for
repeat reaction runs with no diminution of product yield.
References
1. Holbrey, J. D.; Seddon, K. R. Clean Prod. Process. 1999,
1, 232–236.
2. Welton, T. Chem. Rev. 1999, 99, 2071–2083.
3. Earle, M. J.; McCormac, P. B.; Seddon, K. R. Chem.
Commun. 1998, 2245–2246.
The acidity of the C(2)–H in imidazolium cations is well
known, and the pKa is such that the proton readily
exchanges with D2O at room temperature and pH 7.13
Consequently, the reaction of these cations with base is
facile, and gives rise to imidazolidene carbenes.14 Indeed,
when the substituents on the ring nitrogen atom are
sufficiently bulky, the reactive species may be isolated,
and it is just such materials that constitute the only
isolable examples of free carbenes.14 Given this behavior,
it is likely that the active base in the Knoevenagel and
Robinson annulation reactions are carbenes. This possi-
bility has been raised in earlier reactions involving base
in ionic liquids as well.3,4 If current studies in our
laboratory bear out the case for carbenes as the actual
base in these reactions, considerable opportunities exist
for exploiting ionic liquids as customized basic reaction
media. Suitably functionalized imidazolium cations
might control the degree of medium basicity and poten-
tially even the stereochemistry of deprotonations, possi-
bilities we plan to investigate.
4. Davis, Jr., J. H.; Forrester, K. J. Tetrahedron Lett. 1999,
40, 1621–1622.
5. Visser, A. E.; Swatloski, R. P.; Reichert, W. M.; Mayton,
R.; Sheff, S.; Wierzbicki, A.; Davis, Jr., J. H.; Rogers, R.
D. Chem. Commun. 2001, 135–136.
6. Merrigan, T. L.; Bates, E. D.; Dorman, S. C.; Davis, Jr.,
J. H. Chem. Commun. 2000, 2051–2052.
7. Davis, Jr., J. H. In Green Industrial Applications of Ionic
Liquids: Proceedings of the NATO Advanced Research
Workshop; Rogers, R. D., Ed.; Kluwer: Dordrecht, in
press.
8. Davis, Jr., J. H.; Wierzbicki, A. In Proceedings of the
Symposium on Advances in Solvent Selection and Substitu-
tion for Extraction; American Institute of Chemical Engi-
neers: New York, 2000; Paper 14F.
9. Forrester, K. J.; Merrigan, T. L.; Davis, Jr., J. H. Tetra-
hedron Lett. 1998, 39, 8955–8958.
10. Forbes, D. C.; Barrett, E. J.; Lewis, D. L.; Smith, M. C.
Tetrahedron Lett. 2000, 41, 9943–9947.
11. Huddleston, J. G.; Willauer, H. D.; Swatloski, R. P.;
Visser, A. E.; Rogers, R. D. Chem. Commun. 1998,
1765–1766.
Acknowledgements
12. Representative procedure for the preparation of benzylidene-
malonitrile: To a 5 mL flat-bottomed flask containing a
magnetic stir bar was added, in the following order, 0.5
mL 1-hexyl-3-methyl imidazolium hexafluorophosphate
([6-mim]PF6), 40 mg malononitrile (0.61 mmol, 1.0
equiv.), 62 mL benzaldehyde (0.61 mmol, 1.0 equiv.) and
9 mg glycine (0.12 mmol, 0.2 equiv.). The reaction mix-
ture was kept at room temperature for a period of 22 h at
J.H.D. thanks Professor Richard Pagni for encouraging
us to follow up on our early work in base-promoted
reactions in ionic liquids. He also thanks the Alabama
Department of Public Health for an Alabama Legacy
Environmental Research Trust grant for support of this
research. D.C.F. is grateful to the donors of the

D. W. Morrison et al. / Tetrahedron Letters 42 (2001) 6053–6055
6055
which time the reaction mixture was extracted with tolu-
ene (3×2.0 mL). Analysis of the crude reaction mixture
revealed that 98% of the organic residues introduced to
1-hexyl-3-methyl imidazolium hexafluorophosphate ([6-
mim]PF6) are removed after performing three 2.0 mL
washes with toluene. The organic extracts were then
combined and concentrated in vacuo. The resulting vis-
cous oil was immediately purified via silica gel chro-
matography [hexane/EtOAc, 1/1, 10×30 mm SiO2, 3 mL
fractions] to afford 72.3 mg (77% yield) of the title
compound. Spectral and physical data obtained are in
agreement with those previously reported.
Recycling of 1-hexyl-3-methyl imidazolium hexafluoro-
phosphate ([6-mim]PF6) for the preparation of benzylidene-
malonitrile: Analysis of the crude reaction mixture
revealed that nearly all of the organic materials intro-
duced to the ionic liquid solvent were removed (98%)
after washing the ionic liquid solvent with toluene (3×2.0
mL). Upon completion of the toluene washes, a second
run using the ionic liquid solvent, as is without any
further manipulation, was performed under identical
reaction conditions and resulted in the formation of the
title compound in 39% yield. The spectral data (NMR
and TLC) obtained with this material was in agreement
to that obtained in the first.
stir for an additional 1.5 h. The crude reaction mixture
was then cooled to room temperature, neutralized with
aqueous hydrochloric acid (v/wt) and washed with tolu-
ene (3×4.0 mL). This workup procedure does afford a
triphasic system. Control experiments revealed that 90%
of the organic residues are removed after performing
three 4.0 mL washes with toluene. The organic extracts
were then combined and concentrated in vacuo. The
resulting viscous oil was immediately purified via silica
gel chromatography [hexane/EtOAc, 8/1, 10×30 mm
SiO2, 3 mL fractions] to afford 88 mg (48% yield) of the
title compound. Spectral data obtained are in agreement
with those previously reported.
Recycling of 1-hexyl-3-methyl imidazolium hexafluoro-
phosphate ([6-mim]PF6) for the preparation of 6-ethoxycar-
bonyl-3,5-diphenyl-2-cyclohexenone: Analysis of the crude
reaction mixture revealed that nearly all of the organic
materials introduced to the ionic liquid solvent were
removed (90%) after the triphasic workup procedure, that
is, aqueous neutralization and subsequent toluene wash-
ings of the ionic liquid solvent. Upon completion of the
toluene washes (3×4.0 mL), the resulting ionic liquid
solvent was concentrated in vacuo (1.0 Torr for 3 h at
room temperature). Using this ionic liquid solvent, as is
without any further manipulation, a second run was
performed under identical reaction conditions and
resulted in the formation of the title compound in 47%
yield. The spectral data (NMR, TLC and GC) obtained
with this material was in agreement to that obtained in
the first.
Representative procedure for the preparation of 6-ethoxy-
carbonyl-3,5-diphenyl-2-cyclohexenone: To
a
10 mL
round-bottomed flask containing a magnetic stir bar was
added, in the following order, 2.0 mL 1-hexyl-3-methyl
imidazolium hexafluorophosphate ([6-mim]PF6), 120 mg
trans-chalcone (0.57 mmol, 1.0 equiv.), 73 mL ethyl aceto-
acetate (0.57 mmol, 1.0 equiv.) and 50 mg of pulverized
sodium hydroxide (1.0 mmol, 1.7 equiv.). The reaction
mixture was warmed and kept at 100°C for a period of
1.5 h at which time it was cooled to 60°C and allowed to
13. Blanchard, L. A.; Hancu, D.; Beckman, E. J.; Brennecke,
J. F. Nature 1999, 399, 28–29.
14. Joule, J. A.; Mills, K.; Smith, G. F. Heterocyclic Chem-
istry, 3rd ed.; Chapman & Hall: London, 1995.
15. Arduengo, III, A. J. Acc. Chem. Res. 1999, 32, 913–921.
.