D. A. Gerritsma et al. / Tetrahedron Letters 45 (2004) 7629–7631
7631
3
4% yield, respectively). An increase in temperature had
2. Seddon, K. R. Nat. Mater. 2003, 2, 363; Ionic Liquids in
Synthesis; Wasserscheid, P., Welton, T., Eds.; Wiley–
VCH: New York, 2003.
little effect on the overall yield. As a result, a new screen-
ing and optimization program was undertaken. We
quickly determined that organic bases were much better
at promoting the coupling of aryl bromides than sodium
acetate. In fact when the IL library (Table 1, X = Br)
was screened in the reaction of 4-bromoanisole and
t-butylacrylate using Et N and Pd(OAc) at 100°C, rea-
3
. Park, S. B.; Alper, H. Org. Lett. 2003, 5, 3209; Calo, V.;
Nacci, A.; Monopoli, A.; Detomaso, A.; Iliade, P.
Organometallics 2003, 22, 4193; Selvakumar, K.; Zapf,
A.; Beller, M. Org. Lett. 2002, 4, 3031.
4
. Vallin, K. S. A.; Emilsson, P.; Larhed, M.; Hallberg, A. J.
Org. Chem. 2002, 67, 6243.
3
2
sonable conversions were obtained for both the THP-Cl
and THP-decanoate. Interestingly, the phosphinate
counter anion of entry 6 also allowed for reasonable
turn over. Addition of additives such as NaOAc or
5. Xie, X.; Lu, J.; Chen, B.; Han, J.; She, X.; Pan, X.
Tetrahedron Lett. 2004, 45, 809.
6. Bradaric, C. J.; Downard, A.; Kennedy, C.; Robertson, A.
J.; Zhou, Y. Green Chem. 2003, 5, 143.
7
8
9
. Karodia, N.; Guise, S.; Newlands, C.; Andersen, J. Chem.
Commun. 1998, 2341.
. McNulty, J.; Capretta, A.; Wilson, J.; Dyck, J.; Adjabeng,
G.; Robertson, A. Chem. Commun. 2002, 1986.
. Kaufmann, D. E.; Nouroozian, M.; Henze, H. Synlett
PPh , were ineffective at lower concentrations (2–15%)
3
and deleterious at higher concentrations (above 20%).
However, small amounts of chloride or decanoate could
be added to allow for turnovers from ILs that did not
normally facilitate the Heck reaction. For example,
when 10% decanoate was added to THP-bromide, the
conversion after 2h increased to 43%. Optimal condi-
tions for the coupling of aryl bromides were determined
1
0. Handy, S. T.; Okello, M. Tetrahedron Lett. 2003, 44,
996, 1091.
1
8395.
11. Smaller amounts of palladium can be used, however, 4%
Pd(OAc) allowed for excellent turnovers in roughly 2h.
(
1% Pd(OAc) , Et N and 1.4equiv of olefin) and applied
3
2
2
1
2. Samples of THP-Cl (trade name CYPHOS 3653) and all
other ionic liquids described may be obtained by contact-
ing Cytec at the address given. A representative procedure
for the Heck reaction is as follows. Into an oven dried
to a series of coupling partners. A few representative
examples appear in Table 2 (entries 8–10).
In conclusion, it has been demonstrated that judious
choice of phosphonium salt ionic liquid provides an eco-
nomical, recyclable media for the Heck cross-coupling
reaction. Further analysis of the active Pd-catalytic spe-
5
mL reaction vessel equipped with a stir bar were added
trihexyl(tetradecyl)phosphonium chloride (THP-Cl,
20mg, 1.0mmol), Pd(OAc) (4%, 11.2mg, 0.05mmol),
5
2
sodium acetate (123.0mg, 1.5mmol) and placed under
vacuum for 1h before exposure to a nitrogen atmosphere.
The aryl halide (1.0mmol), the olefin (1.5mmol) and H O
cies formed by dissolution of Pd(OAc) in the phospho-
2
nium salt ionic liquid and applications of the process to
other coupling partners are currently under investiga-
tion in our laboratories.
2
(50lL) were added and the flask heated to 50°C with
stirring. After the appropriate amount of time (approxi-
mately 2h), the reaction mixture was cooled and treated
with brine (1mL) and hexane (2mL). The mixture was
stirred vigorously, then allowed the separate over 30min.
Both the aqueous and organic layers were collected and
the IL layer extracted with fresh hexane and brine for a
total of five times. The organic layers were combined and
concentrated under reduced pressure and the residue
purified via flash silica gel chromatography if necessary
Acknowledgements
We thank the Natural Sciences and Engineering
Research Council of Canada (Collaborative Research
and Development Award) and Cytec Canada Inc. for
financial support.
(
5–25% ethyl acetate in hexane). Use of this method
allowed for efficient catalyst recycling. For example, in the
case of entry 6, the ionic liquid was degassed then
recharged with methylacrylate, 4-iodoanisole and NaOAc
and heated as indicated above. Aryl bromides were run
under identical conditions in a sealed vessel using 1%
References and notes
1
. Heck, R. F.; Nolley, J. P., Jr. J. Org. Chem. 1972, 37,
320; Metal-Catalyzed Cross Coupling Reactions; Diede-
rich, F., Stang, P., Eds.; Wiley–VCH: New York, 1998;
2
2
Pd(OAc) , 1.4equiv tert-butyl acrylate and 1.5equiv
Dounay, A. B.; Overman, L. E. Chem. Rev. 2003, 103,
2
triethylamine (no water was added) and heated to 100°C
for 4–8h.
945.