coupling of aryl bromides and chlorides.4 After surveying
various Pd(0) catalysts to broaden the scope of the reac-
tion,9,10 the most suitable catalyst/ligand system was found
to be Pd(OAc)2/PPh3 or P(o-tol)3 (1:2 molar ratio Pd:P).11
Using these conditions, excellent yields of cross coupled
adducts were obtained irrespective of the substituent attached
to the aryl moiety (Table 1).12 In general, yields are slightly
A catalyst loading study was performed to determine the
minimal catalyst required for the coupling reaction (Table
2). Again, the three major electronic subclasses of aryl
Table 2. Catalyst Loading Studies
Table 1. Substrate and Phosphine Studies
entry
R
x (mol % Pd)
yielda (%)
1
2
3
4
5
4-COCH3
4-COCH3
4-COCH3
4-COCH3
4-CH3
1
3
5
10
1
82
83
77
86
entry
X
R
phosphine
yielda (%)
0b
1
2
3
4
5
6
7
8
Br
Br
Br
Br
Br
Br
Cl
Cl
COCH3
COCH3
CH3
PPh3
P(o-tol)3
PPh3
P(o-tol)3
PPh3
P(o-tol)3
PPh3
86
78
82b
78c
74
70
29d
30e
6
7
8
9
10
11
12
13
14
15
4-CH3
4-CH3
4-CH3
4-OCH3
4-OCH3
4-OCH3
4-OCH3
2,6-CH3
2,6-CH3
2,6-CH3
3
5
10
1
3
5
10
3
5
10
77
73
82c
15d
80
87
74
10e
21f
85g
CH3
OCH3
OCH3
COCH3
COCH3
P(o-tol)3
a Reaction times were not optimized, but most reactions were complete
within 1-5 h. b 10% homocoupled product obtained. c 3% homocoupled
product obtained. d 71% starting material recovered. e 70% starting material
recovered.
a Reaction times were not optimized. It should also be noted that yields
are reproducible and reactions were run on average of three times each.
b 78% starting material obtained. c 10% homocoupled product obtained.
d 82% starting material obtained. e 79% starting material obtained. f 62%
starting material obtained. g 2% starting material obtained.
lower using P(o-tol)3, but one advantage of using this ligand
is that the yield of the homocoupled adduct decreases in the
cross coupling of 4-bromotoluene (Table 1, entry 3 (10%)
vs entry 4 (3%)).13
substituents were investigated (electron-deficient, entries
1-4, electron-neutral, entries 5-8, and electron-donating,
entries 9-12). A fourth substrate, 2-bromo-m-xylene (entries
13-15), was used to determine the effect of steric congestion
on catalyst loadings. It was found that in the case of
4-bromoacetophenone (entries 1-4) the reaction gave similar
yields independent of the amount of catalyst used. With
4-bromotoluene, the reaction was unsuccessful using 1 mol
% of Pd(OAc)2 (entry 5), but increasing the catalyst loading
to 3 mol % of Pd(OAc)2 (entry 6) gave only the hetero-
coupled adduct. A similar trend was observed for 4-bro-
moanisole; using 1 mol % of Pd(OAc)2 gave mostly
recovered starting material (82%, entry 9), but increasing
the amount of catalyst to 3 mol % gave only the hetero-
coupled adduct (80%, entry 10). For relatively unhindered
substrates, a catalyst loading of 3 mol % of Pd(OAc)2 is
appropriate for aryl bromides. The hindered substrate,
2-bromo-m-xylene, underwent successful coupling only with
catalyst loadings of 10% (entry 15).
(9) In addition to testing Pd(OAc)2, Pd(dba)2, and APC without ligands,
some of the catalyst/ligand systems tested were Pd(OAc)2/P(n-Bu)3, Pd-
(dba)2/P(t-Bu)3, Pd2dba3/P(t-Bu)3, APC/P(t-Bu)3. Last, Herrmann’s catalyst
(Herrmann, W. A.; Resinger, C. P.; Spiegler, M. J. Organomet. Chem. 1998,
557, 93-96) was synthesized and upon testing failed to give cross coupled
adducts.
(10) A report has been published in which alkenyl-monooxydimethyl-
silanes, dialkoxysilanes, and trialkoxysilanes undergo palladium-catalyzed
cross coupling reactions with alkenyl iodides and bromides, as well as aryl
iodides. In this case, the catalyst/ligand system used was APC/P(OEt)3. We
did not test this particular system using our reaction conditions. For more
information, please see: Tamao, K.; Kobayashi, K.; Ito, Y. Tetrahedron
Lett. 1989, 30, 6051-6054.
(11) For a detailed discussion of the Pd species formed when 2 equiv or
less of phosphine is used with Pd(OAc)2, please see: Amatore, C.; Jutand,
A.; M’Barki, M. A. Organometallics 1992, 11, 3009-3013.
(12) General procedure for cross coupling reactions: phenyltrimethox-
ysilane (2.178 g, 10.983 mmol) was added to 2-bromo-m-xylene (1.004 g,
5.425 mmol), Pd(OAc)2 (0.119 g, 0.530 mmol), and PPh3 (0.283 g, 1.079
mmol) in 40 mL of DMF (under Ar). TBAF (10.80 mL, 10.80 mmol) was
added via syringe. The reaction mixture was degassed (one freeze-pump-
thaw cycle). The reaction was heated at 83 °C (23.5 h). The reaction was
quenched (50 mL H2O) and extracted (4 × 50 mL Et2O). The organic layers
were dried over MgSO4 and concentrated in vacuo. Purification by flash
chromatography (55 mm, 15 cm, pentane) gave 2,6-dimethylbiphenyl (825
mg, 85% yield) as a colorless oil: TLC Rf ) 0.43 (pentane); IR (CCl4)
3062 (w), 3022 (w), 2962 (w), 2924 (w), 1558 (vs), 1541 (vs), 1463 (m),
1443 (w), 1251 (m), 1216 (m), 1111 (m), 1072 (m), 1072 (m), 1009 (s),
973 (m), 829 (s), 808 (m); 1H NMR (CDCl3) δ 2.03 (s, 3H), 7.07-7.18
(m, 5H), 7.31-7.35 (m, 1H), 7.40-7.44 (m, 2H); 13C NMR (CDCl3) 20.8,
126.6, 127.0, 127.3, 128.4, 129.0, 136.1, 141.1, 141.9; GCMS 183 ((M +
1), 13), 182 ((M+), 88), 181 (30), 168 (15), 167 (100), 166 (30), 165 (56),
152 (22), 83 (25).
Since the cross coupling reaction using Pd(OAc)2/PPh3 was
accomplished with aryl bromides, the technology was
(13) This has not been a general trend observed in the literature, and it
is a new finding for this particular substrate. At this point in time, we do
not have a specific rationalization for this observation. Mechanistic studies
with assorted phosphines are underway to elucidate the electronic and steric
roles played by phosphines in the catalytic cycle.
2138
Org. Lett., Vol. 1, No. 13, 1999