An iron-containing ionic liquid as recyclable catalyst for aryl Grignard cross-coupling of alkyl halides

Article abstract of DOI:10.1021/ol052965z

The ionic liquid butylmelhylimidazolium tetrachloroferrate (bmim-FeCl ₄) was found to be a very effective and completely air stable catalyst for the biphasic Grignard cross-coupling with primary and secondary alkyl halides bearing β-hydrogens. After simply decanting the product in the ethereal layer, the ionic liquid catalyst was successfully recycled four times.

Full text of DOI:10.1021/ol052965z

ORGANIC
LETTERS
2006
Vol. 8, No. 4
733-735
An Iron-Containing Ionic Liquid as
Recyclable Catalyst for Aryl Grignard
Cross-Coupling of Alkyl Halides
Katharina Bica and Peter Gaertner*
Department of Applied Synthetic Chemistry, Vienna UniVersity of Technology,
Getreidemarkt 9, A-1060 Vienna, Austria
peter.gaertner@tuwien.ac.at
Received December 7, 2005
ABSTRACT
The ionic liquid butylmethylimidazolium tetrachloroferrate (bmim-FeCl4) was found to be a very effective and completely air stable catalyst for
the biphasic Grignard cross-coupling with primary and secondary alkyl halides bearing
the ethereal layer, the ionic liquid catalyst was successfully recycled four times.
â-hydrogens. After simply decanting the product in
Since iron is one of the most inexpensive and nonpollutant
metals on earth, the scope for iron-catalyzed chemistry is of
substantial interest.1,2 Recent advances in the field of iron-
catalyzed cross-coupling chemistry include the original work
of Kochi et al.3 and of Cahiez and Avedissian,4 considering
alkenyl bromides, as well as recent papers of Fu¨rstner and
co-workers who used iron-salen precatalysts5 and the
tetrakisferrate complex [Li(tmeda)2]Fe(C2H4)2.6 Nagano and
Hayashi showed the utility of Fe(acac)3 7 in the coupling of
C(sp3)-X compounds, whereas Fu¨rstner used Fe(acac)3 and
anhydrous FeCl3 for the coupling of aryl halides.5,8 Several
papers of Fu¨rstner et al. dealt with the Fe(acac)3-catalyzed
coupling of aryl triflates9 and enol triflates10 as well as with
acid chlorides10,11 and propargyl epoxides.12 Further studies
on the use of various iron-salen catalysts were done by
Bedford et al., who also discovered the use of anhydrous
FeCl3 in combination with appropiate amine ligands to
diminish â-elimination.13 The catalyst system FeCl3/stoichio-
metric TMEDA for the coupling of Grignard and zinc
reagents was also described by Nakamura et al.; nevertheless,
slow addition of the Grignard reagent via a syringe pump
was necessary.14 In our current studies concerning the use
of ionic liquids for transition metal catalyzed reactions,15 we
discovered that the iron-containing ionic liquid butylmeth-
ylimidazolium tetrachloroferrate (bmim-FeCl4) is a very
(1) For a general review on iron-catalyzed organic reactions, see: (a)
Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chem. ReV. 2004, 104, 6217. (b)
Shinokobu, H.; Oshima, K. Eur. J. Org. Chem. 2004, 2081.
(2) For a recent review on iron-catalyzed cross-coupling chemistry:
Fu¨rstner, A.; Rube´n, M. Chem. Lett. 2005, 34, 624.
(3) (a) Tamura, M.; Kochi, J. K. J. Am. Chem. Soc. 1971, 93, 1487. (b)
Tamura, M.; Kochi, J. K. Bull. Chem. Soc. Jpn. 1971, 44, 3063. (c) Tamura,
M.; Kochi, J. K. Synthesis 1971, 303. (d) Kochi, J. K. Acc. Chem. Res.
1974, 7, 351. (e) Neumann, S. M.; Kochi, J. K. J. Org. Chem. 1975, 40,
599. (e) Smith, R. S.; Kochi, J. K. J. Org. Chem. 1976, 41, 502. (f) Kochi,
J. K. J. Organomet. Chem. 2002, 653, 11.
(9) Seidel, D.; Laurich, D.; Fu¨rstner, A. J. Org. Chem. 2004, 69, 3950.
(10) (a) Scheiper, B.; Bonnekessel, M.; Krause, H.; Fu¨rstner, A. J. Org.
Chem. 2004, 69, 3943. (b) Fu¨rstner, A.; De Souza, D.; Parra-Rapado, L.;
Tenson, J. Angew. Chem., Int. Ed. 2003, 42, 5358.
(11) Fiandanese, V.; Marchese, G.; Martina, V.; Ronzini, L. Tetrahedron
Lett. 1984, 25, 4805. (b) Cardellicchio, C.; Fiandanese, V.; Marchese, G.;
Ronzini, L. Tetrahedron Lett. 1987, 28, 2053.
(4) Cahiez, G.; Avedissian, H. Synthesis 1998, 1199.
(5) (a) Fu¨rstner, A.; Leitner, A.; Me´ndez, M.; Krause, H. J. Am. Chem.
Soc. 2002, 124, 13856. (b) Fu¨rstner, A.; Leitner, A. Angew. Chem., Int.
Ed. 2003, 42, 308.
(6) Martin, R.; Fu¨rstner, A. Angew. Chem., Int. Ed. 2004, 43, 3955.
(7) Nagano, T.; Hayashi, T. Org. Lett. 2004, 6, 1297.
(12) Fu¨rstner, A.; Me´ndez, M. Angew. Chem., Int. Ed. 2003, 42, 5355.
(13) Bedford, R. B.; Bruce, D. W.; Frost, R. M.; Hird, M. Chem.
Commun. 2005, 4161.
(14) (a) Nakamura, M.; Matsuo, K.; Ito, S.; Nakamura, E. J. Am. Chem.
Soc. 2004, 126, 3686. (b) Nakamura, M.; Ito, S.; Matsuo, K.; Nakamura,
E. Synlett 2005, 11, 1794.
(8) Fu¨rstner, A.; Leitner, A. Angew. Chem., Int. Ed. 2002, 41, 609.
10.1021/ol052965z CCC: $33.50
© 2006 American Chemical Society
Published on Web 01/26/2006

Table 1. Influence of Catalyst Concentration on the
bmim-FeCl4-Catalyzed Cross Coupling of
Table 2. Results of Various Aryl Grignard Cross-Couplings
Catalyzed by bmim-FeCl4
4-Fluorophenylmagnesium Bromide 2a and Dodecyl Bromide 1
yield
entrya
bmim-FeCl4 (mol %)
3b (%)
3ab (%)
3bb (%)
1
2
3
4
5
10
5
1
0.5
0.1
88.3
89.8
80.3
79.4
<0.1
7.6
6.7
9.9
9.8
0.5
3.5
3.0
4.9
6.1
0.4
a All reactions were carried out in Et2O at 0 °C with 2 mmol of R-X
and 3 mmol of ArMgX under air. b Determined by GC-MS using
n-hexadecane as internal standard.
efficient catalyst for the Grignard cross coupling of alkyl
halides. Bmim-FeCl4 was easily prepared in a solid state
reaction by mixing commercially available solid bmim-Cl
and FeCl3‚6 H2O, yielding the hydrophobic ionic liquid as a
lower phase, and water, which can be easily separated.16 This
ionic liquid was already used on solid support as a catalyst
for Friedel-Crafts acylation,17 but, to the best of our
knowledge, no application in cross-coupling chemistry either
as catalyst nor as solvent has been reported so far. For initial
screening of catalytic activity, we chose an alkyl halide
bearing â-hydrogens and examined the coupling between
dodecyl bromide and 4-fluorophenylmagnesium bromide
using 10 mol % of bmim-FeCl4 catalyst. The biphasic
reaction was initially run in dry diethyl ether as cosolvent,
but later studies showed that there is no difference using
technical instead of anhydrous ether. Furthermore, the
reaction proved to be completely air and moisture stable and
could be carried out without inert atmosphere. Since addition
of the Grignard solution was rather exothermic, cooling with
an ice bath during the addition is recommended, although
higher temperature did not have any negative influence on
the conversion.
Reactions proceeded very fast within 10 min and gave
product 3 in 88% yield and only small amounts of byproducts
from â-elimination (3a) and reductive elimination (3b) (Table
1; entry 1) compared to analogous Fe(acac)3-catalyzed
(15) For a review: (a) Wasserscheid, P.; Keim, W. Angew. Chem., Int.
Ed. 2000, 39, 3772. (b) Olivier-Bourbigou, H.; Magna, L. J. Mol. Catal. A
2002, 182-183, 419. (c) Wasserscheid, P.; Welton, T. Ionic Liquids in
Synthesis; Wiley-VCH: Weinheim, Germany, 2003.
(16) (a) Hayashi, S.; Hamaguchi, H. Chem. Lett. 2004, 33, 1590. (b)
Sitze, M. S.; Schreiter, E. R.; Patterson, E. V.; Freeman, R. G. Inorg. Chem.
2001, 40, 2298. (c) Zhang, Q.; Yang, J.; Lu, X.; Gui, J.; Huang, M. Fluid
Phase Equilib. 2004, 226, 207.
a All reactions were carried out in Et2O at 0 °C with 2 mmol of R-X
and 3 mmol of ArMgX under air. b Isolated yield after flash chromatography,
if not otherwise stated. c Yield calculated from GC-MS of crude product
using n-hexadecane as internal standard. d No product could be observed
on GC-MS analysis. e 5 mmol of ArMgX used.
(17) Valkenberg, M. H.; deCastro, C.; Holderich, W. F. Appl. Catal. A
2001, 215, 185.
734
Org. Lett., Vol. 8, No. 4, 2006

reactions reported in the literature.7 Best results were obtained
with a catalyst concentration of 5 mol %, giving 90% yield
whereas a lower catalyst concentration resulted in a slight
increase of byproducts 3a and 3b and a decrease of the
desired coupling product 3 (Table 1; entries 2-4). Changing
the Grignard reagent to the electron rich p-tolylmagnesium
bromide as well as to 4-biphenylmagnesium bromide the
reaction proceeded also favorably, although with lower yields
of 73 and 60%, respectively (Table 2; entries 2 and 3).
Moving to secondary alkyl halides, we observed a selective
formation of the desired coupling product 8 and 9 without
any occurrence of â-elimination or reductive elimination.
Thus, we could achieve considerably higher yields in the
coupling of 2-octyl bromide and cyclohexyl bromide with
Grignard reagent 2b (Table 2; entries 6 and 7) than reported
in the literature for Fe(acac)3 as a catalyst.7 Both cyclohexyl
iodide and chloride turned out to be suitable for the cross
coupling even though the isolated yields of the coupling
product 9 are slightly lower (Table 2; entries 8 and 9).
The use of phenyllithium instead of an aryl Grignard
reagent led to a significant drop of yield, and for the first
time the homocoupling product 1,1′-dicyclohexyl was de-
tected in almost equal amount (Table 2; entry 10). Tertiary
alkyl halides are less reactive: As Nagano and Hayashi have
already reported for Fe(acac)3 as catalyst,7 no conversion at
all could be detected using tert-butyl bromide (entry 11).
Secondary alkyl halides incorperating a heterocyclic N-
methyl piperidinyl structural motif proceeded also satisfy-
ingly, yielding 79% of coupling product 12 (entry 12).
Ionic liquids have proved to be excellent solvents for
catalyst immobilization via liquid-liquid biphasic catalysis.18
In most cases, products and remaining starting materials can
be simply removed by decantation while the catalyst trapped
in the ionic liquid can be reused. Starting with 5 mol % of
bmim-FeCl4 and 0.5 mL of diethyl ether as cosolvent, we
tried to recycle the iron-containing ionic liquid, surveying
the initially optimized coupling of 4-fluorophenylmagnesium
bromide and dodecyl bromide.
Table 3. Recycling of bmim-FeCl4 in the Cross-Coupling of
4-Fluorophenylmagnesium Bromide 2a and Dodecyl Bromide 1
entrya
run
conversion of 1b (%)
yield of 3c (%)
1
2
3
4
5
1
2
3
4
5
>99
>99
96
93
92
86
n.a.
77
n.a.
76
a All reactions were carried out in Et2O at 0 °C with 2 mmol of R-X
and 3 mmol of ArMgX under air. b Conversion calculated from GC-MS
of crude product using n-hexadecane as internal standard. c Isolated yield
after flash chromatography.
extracted by washing the residue twice with 0.5 mL of diethyl
ether each. Fresh alkyl halide, n-hexadecane as internal
standard and 0.5 mL of diethyl ether as cosolvent were added
to the remaining bmim-FeCl4 layer which had turned from
black to orange during the washing steps. Successive addition
of Grignard reagent gave an immediate color change to black,
and the catalytic cycle was found to be active again. Although
conversion of the alkyl halide is almost complete, the isolated
yield of the desired coupling product 3 slightly decreased
from 86% in the first run to 76% after the fifth one (Table
3; entries 1-5). This may be explained by the fact that small
amounts of iron get removed from the ionic liquid phase
during extraction (compare to Table 1).
In summary, we have established a new, easily prepared,
and recyclable catalyst for iron catalyzed Grignard cross-
coupling of primary and especially of secondary alkyl halides
under mild and air-stable conditions. Further aspects includ-
ing stereoselective coupling using a chiral ionic liquid-
derived iron catalyst as well as mechanistic details via Raman
spectroscopy concerning the catalytically relevant iron spe-
cies are currently under investigation.
Acknowledgment. We thank Prof. B. Lendl and M.
Lo´pez-Pastor for measuring Raman spectra.
After complete reaction the ionic liquid and formed MgBr2
were left to settle, and the upper ethereal layer containing
the product was decanted. The remaining product was
Supporting Information Available: Representative ex-
perimental procedure and characterization of new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(18) Dupont, J.; deSouza, R. F.; Suarez, P. A. Z. Chem. ReV. 2002, 102,
3667.
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