PRACTICAL SYNTHETIC PROCEDURES
Stable Palladium Complex in Coupling Reactions
2591
sumption of starting material, H2O was added to quench the reac-
tion. The mixture was poured into a separatory funnel, extracted
with Et2O, and the organic layer was dried (MgSO4). The MgSO4
was removed by filtration using a filter paper. The filtrate was then
dried over silica gel. The product was purified by column chroma-
tography using silica gel and a 10% EtOAc–hexanes solution (0.85
g, 85% yield).
1H NMR (CDCl3): = 1.5 (d, 3 H, J = 6.9 Hz), 4.7 (q, 1 H), 7.2 (m,
2 H), 7.3 (m, 1 H), 7.35 (m, 4 H), 7.45 (t, 1 H, J = 7.3 Hz), 7.9 (d, 2
H, J = 7.2 Hz).
1-p-Tolylpiperidine;17 Typical Procedure 2
In a glove box, the palladium catalyst 1 (32 mg, 5.6 × 10–2 mmol),
t-BuONa (0.508g, 5.29 mmol), and THF (12 mL) were loaded into
a 25 mL reaction vial. (Alternatively, the catalyst and alkoxide can
be loaded in air into the reaction vial and the vial is then flushed
with N2 or argon prior to addition of anhyd THF). The vial was tak-
en out of the glove box and 4-chlorotoluene (0.675 mL, 5.70 mmol)
and piperidine (0.564 mL, 5.70 mmol) were injected through the
cap septum. The vial was heated to 70 °C with stirring for 4 h.
Progress of the reaction was monitored by GC. After this time, H2O
was added to quench the reaction. The mixture was poured into a
separatory funnel, extracted with Et2O and the organic layer was
dried (MgSO4). The MgSO4 was removed by filtration using a filter
paper. The filtrate was then dried over silica gel. The product was
purified by column chromatography using silica gel and a 10%
EtOAc–hexanes solution (0.97 g, 97% yield).
Figure 1 Structure of (IPr)Pd(allyl)Cl (1) pre-catalyst
In palladium-mediated C–C and C–N bond formation re-
actions, the present system displays high activity even
with traditionally difficult substrates, namely aryl chlo-
rides.15 Through an increased electron donation originat-
ing from the NHC, the palladium center is easily capable
of activating the ‘inert’ C–Cl bond. Reactions involving
activation of C–Br and C–I bonds can also be mediated by
1.
Gram-scale syntheses were carried out using three differ-
ent systems. The first to be tested was the synthesis of a
biaryl molecule through an -ketone arylation. The sec-
ond transformation described is an aryl-amination (Buch-
wald–Hartwig reaction), and the third is a Suzuki–
Miyaura coupling. All three syntheses worked quite well
and we show that the commercially available complex 1
is an active and efficient pre-catalyst in every gram-scale
reactions examined (Scheme 1).
1H NMR (CDCl3): = 7.05 (d, 2 H, J = 8.1 Hz), 6.8 (d, 2 H, J = 7.8
Hz), 3.1 (t, 2 H, J = 5.4 Hz), 2.26 (s, 3 H), 1.7 (m, 2 H).
2-Methoxybiphenyl;18 Typical Procedure 3
In a glove box, the palladium catalyst 1 (57 mg, 1.0 × 10–2 mmol),
t-BuONa (1.440 g, 15 mmol) and phenylboronic acid (0.732 g, 6
mmol) were added in turn to a 50 mL Schlenk flask containing a
magnetic stirring bar, and stoppered with a rubber septum. (Alter-
natively, the catalyst, alkoxide, and boronic acid can be charged in
air into the reaction flask and the flask was then purged with N2 or
argon prior to addition of anhyd dioxane). The flask was removed
from the glove box and 2-chloroanisole (0.634 mL, 5 mmol) and
1,4-dioxane (7.5 mL) were injected into the Schlenk flask in this se-
quence. The Schlenk flask was then placed in an oil bath over a
magnetic stirring plate set at 60 °C for 2 h. Progress of the reaction
was monitored by GC. After 2 h, silica gel was added to the vial and
the solvent is removed in vacuo. The product was purified by flash
chromatography using silica gel and a 10% EtOAc–hexanes solu-
tion (835 mg, 91% yield).
In all procedures to synthesize compounds using the three
C–C and C–N bond forming reactions described above,
anhyd solvents were used and t-BuONa was used as the
base. For ease of handling, initial reaction mixtures were
charged under inert atmosphere in a glove box, but we
have also shown that these reactions can be carried out in
purged vessels using standard Schlenk techniques. In Pro-
cedure 1, the synthesis of 1,2-diphenylpropan-1-one from
propiophenone and chlorobenzene is described. In Proce-
dure 2, 1-p-tolylpiperidine is isolated from 4-chlorotolu-
ene and piperidine. In Procedure 3, using a Suzuki–
Miyaura coupling, 2-methoxybiphenyl is produced from
2-chloroanisole and phenylboronic acid.
1H NMR (CDCl3): = 7.56 (d, 2 H, J = 8.0 Hz), 7.43 (t, 2 H, J = 7.5
Hz), 7.35 (m, 3 H), 7.03 (t, 1 H, J = 8.4 Hz), 3.84 (s, 3 H).
Acknowledgment
The National Science Foundation is gratefully acknowledged for
support of this work.
1,2-Diphenylpropan-1-one;16 Typical Procedure 1
In a glove box, the palladium catalyst 1 (27 mg, 4.73 × 10–2 mmol),
t-BuONa (502 mg, 5.22 mmol), and THF (12 mL) were charged into
a 25 mL reaction vial. (Alternatively, the catalyst and alkoxide can
be loaded in air into the reaction vial and the vial can then be flushed
with N2 or argon prior to addition of anhyd THF). The vial was tak-
en out of the glove box and propiophenone (0.633 mL, 4.75 mmol)
and chlorobenzene (0.483 mL, 4.75 mmol) were injected through
the septum-cap. The vial was heated to 70 °C with stirring for 5 h.
The progress of the reaction was monitored by GC. After the con-
References
(1) Visiting student from the Université Pierre et Marie Curie.
(2) (a) Littke, A. F.; Fu, G. C. Angew. Chem. Int. Ed. 2002, 41,
4176. (b) Wolfe, J. P.; Wagaw, S.; Marcoux, J. F.;
Buchwald, S. F. Acc. Chem. Res. 1998, 31, 805.
(c) Hatrwig, J. F. Angew. Chem. Int. Ed. 1998, 37, 2046.
Synthesis 2003, No. 16, 2590–2592 © Thieme Stuttgart · New York