the phosphine ligand and the choice of base, as Fu
well-known coupling reactions involving challenging sub-
strates such as aryl chlorides. In this study we also explored
1
1b
5c
demonstrated,
but it may also depend on the nature of
the halide ligand originating from the aryl halide.
As shown in Step III, 1 equiv of base was required to
abstract HBr from 3 to generate (Cy P) Pd(0).
3 2
[t-Bu
reaction
active catalyst among the well-known preformed catalysts
2
(4-Me
2
NC
6
H
4
)P]
2
Pd catalyst for Cu-free Sonogashira
1
9,20
of aryl bromides and found that it is the most
In the actual one-pot procedure, the total amount of base
required for the overall process was dissolved in a protic
solvent and added up front to 1 in toluene. Upon generation
of 2, the reaction mixture was heated directly to obtain
2
tested (Table 2). Using this information, we used [t-Bu (4-
Table 2. Catalysts Screened for the Cu-Free Sonogashira
(
3 2
Cy P) Pd(0) in toluene without the isolation of 3. The
Coupling of 4-Bromoanisole with Phenylacetylene for
process is very efficient, where additional MeOH was added
in the final step to precipitate/crystallize the product, while
dissolving the NaBr byproduct, thereby avoiding any re-
crystallization. At room temperature, the reaction stopped
at compound 3 despite the use of excess base.
a
Comparison
b
entry
catalyst
Pd
yield (%)
In the overall process, the methoxy group generated in
situ was transferred to the cyclooctadiene ligand to form the
oxidized byproduct 4, while Pd(II) was reduced to Pd(0),
via ꢀ-H elimination followed by a base-assisted reductive
elimination of HBr. This method does not require the use of
excess expensive phosphine as a sacrificing reducing agent,
thereby making the whole process highly efficient and atom-
1
2
3
4
5
(t-Bu
3
P)
2
73
61
15
<5
97
[Pd(µ-Br)(t-Bu
(PPh Pd
Pd(PCy Cl
[t-Bu (4-Me NC H )P] Pd
3 2
P)]
3 4
)
3
)
2
2
2
2
6
4
2
a
Reaction conditions: 4-bromoanisole (1.5 mmol, 187 µL), pheny-
CO
3
lacetylene (1.8 mmol, 198 µL), 0.5 mol % Pd catalyst (7.5 µmol), Cs
(3.0 mmol, 977.5 mg), CH CN (2 mL), 80 °C, 4 h. Isolated yields.
3
2
b
1
4
economical. The method outlined above has been applied
to a family of (R P) Pd(0) complexes, but not limited to
3
2
1
5
L
2
Pd(0).
We also observed that Step III is the rate determining step,
where the reaction rate appears to depend on the steric bulk
of the phosphine in the following order: t-Bu P ∼
P ∼ o-tol
t-Bu NpP > t-Bu (4-Me NC )P >
PhP > Q-Phos ∼ t-Bu
Cy P. For example, the reaction took place at 75 °C in the
case of Cy P and at room temperature for t-Bu PhP, while
with the bulky t-Bu P and o-tol
P6 ligands, the reaction
proceeded even at 0 °C (Table 1).
2 6 4 2
Me NC H )P] Pd to couple aryl and heteroaryl chloride
substrates with alkynes successfully using only 0.5 mol %
catalyst loading, although higher temperature was required
3
3
(Table 3). Noticeably, 0.5% catalyst loading is half of what
2
2
2
2
6 4
H
3
(
11) (a) Clark, H. C.; Goel, A. B.; Goel, S. Inorg. Chem. 1979, 18,
3
2
2803. (b) Hills, I. D.; Fu, G. C. J. Am. Chem. Soc., 2004, 126, 13178. (c)
Barrios-Landeros, F.; Carrow, B. P.; Hartwig, J. F. J. Am. Chem. Soc., 2008,
3
3
1
1
30, 5842. (d) Sergeev, A. G.; Spannenberg, A.; Beller, M. J. Am. Chem.
Soc. 2008, 130, 15549. (e) Grushin, V. V. Chem. ReV. 1996, 96, 2011
12) Thermal ellipsoids are shown at 50% probability (hydrogen atoms
.
(
were omitted for clarity). Selected bond distances (Å) and angles (deg):
C1-C2, 1.373(9); C5-C6, 1.512(9); Pd-C6, 2.062(7); Pd-Br, 2.644(1);
Br-Pd-Br, 88.55(2); C1-Pd-C6, 281.1(3).
Table 1. Examples of L
2
Pd(0) Catalysts Synthesized
(13) Thermal ellipsoids are shown at 50% probability (hydrogen atoms
were omitted for clarity). Selected bond distances (Å) and angles (deg):
Pd-Br, 2.532(1); Pd-P1, 2.308(1); P1-Pd-P2, 163.38(2); P1-Pd-Br,
a
31P NMR (ppm)b
ligand (L)
temp (°C) yield (%)
9
8.43(5).
14) Other (diene)PdX
effectively.
(15) This method was also tested to make Pd(PPh
16) (a) All complexes were isolated in excellent purity as determined
t-Bu
t-Bu
3
P
NpP
0
0
0
25
60
50
75
95
85
91
96
85
95
85
86.5
45.5
-7.3
67.6
64.5
59.0
39.2
(
2 2
precursors such as (NBD)PdBr also work
2
o-tolyl
3
P
3 4
) successfully.
(
t-Bu
t-Bu
2
PhP
(4-Me
3
1
3 2
by elemental analysis and NMR. (b) P NMR of (o-tol P) Pd showed
2
C
2 6
4
H )P
phosphine dissociation in solution. The extent of phosphine dissociation
was found to be dependent on the concentratration of the complex,
temperature, and the presence of air in the deuterated solvent. This
Q-Phos
Cy
3
P
observation is similar to the case of Pd(PPh ) . (c) (Q-Phos) Pd is a very
3 4 2
a
Isolated yields. 31P NMR chemical shifts of L
b
2
Pd(0) complexes.
1
insoluble compound in most common organic solvents, hence its H NMR
spectrum does not reflect the purity of the compound.
(
17) Hill, L. L.; Crowell, J. L.; Tutwiler, S. L.; Massie, N. L.; Hines,
C. C.; Griffin, S. T.; Rogers, R. D.; Shaughnessy, K. H.; Gabriela, A.; Grasa,
G. A.; Johansson Seechurn, C. C. C.; Li, H.; Colacot, T. J.; Chou, J.;
Woltermann, C. J. Manuscript in preparation.
Having developed a synthetic protocol for various L
complexes with the isolation of two new complexes, [t-Bu
Me NC )P] Pd and (t-Bu NpP) Pd, we decided to study
their activities in catalysis. In this regard, we determined the
X-ray crystal structure of (t-Bu NpP) Pd catalyst and briefly
studied its applications in the amination and R-arylation
2
Pd(0)
2
(4-
(
(
18) Vo, G. D.; Hartwig, J. F. J. Am. Chem. Soc. 2009, 131, 11049
.
2
H
6 4
2
2
2
19) For recent general Sonogashira reviews see: (a) Plenio, H. Angew.
Chem., Int. Ed. 2008, 47, 6954. (b) Doucet, H.; Hierso, J.-C. Angew. Chem.,
Int. Ed. 2007, 46, 834
20) (a) Heiden, M.; Plenio, H. Chem. Commun. 2007, 972. (b) Chen,
.
2
2
(
Y.; Ren, H. J. Org. Chem. 2006, 71, 2535. (c) Adjabeng, G.; Brenstrum,
T.; Frampton, C. S.; Robertson, A. J.; Hillhouse, J.; McNulty, J.; Capretta,
A. J. Org. Chem. 2004, 69, 5082. (d) Soheili, A.; Albaneze-Walker, J.;
Murry, J. A.; Dormer, P. G.; Hughes, D. L. Org. Lett. 2003, 5, 4191. (e)
K o¨ llhofer, A.; Pullmann, T.; Plenio, H. Angew. Chem., 2003, 115, 1086.
Angew. Chem., Int. Ed. 2003, 42, 1056. (f) Gelman, D.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2003, 42, 5993. (g) Lipshutz, B. H.; Chung, D. W.;
1
7
reactions with arylbromide and chloride substrates. Of the
known compounds, (o-tol P) Pd was recently evaluated to
be a very efficient precatalyst for amination/ammoniation of
3
2
5
a
18
aryl tosylates and aryl halides while (t-Bu
3 2
P) Pd is a
popular third generation cross-coupling catalyst for several
Rich, B. Org. Lett. 2008, 10, 3793
.
3334
Org. Lett., Vol. 12, No. 15, 2010