Highly active, air-stable palladium catalysts for Kumada-Tamao-Corriu cross-coupling reaction of inactivated aryl chlorides with aryl Grignard reagents

Article abstract of DOI:10.1016/S0022-328X(02)01259-7

Palladium (II) chlorides possessing phosphinous acid ligands have proved to be remarkably active and efficient catalysts for cross-coupling reactions of inactivated aryl chlorides with aryl Grignard reagents (Kumada-Tamao-Corriu reaction) at room temperat

Full text of DOI:10.1016/S0022-328X(02)01259-7

Journal of Organometallic Chemistry 653 (2002) 63ꢀ68
/
www.elsevier.com/locate/jorganchem
Highly active, air-stable palladium catalysts for Kumadaꢀ
/
Tamaoꢀ
/
Corriu cross-coupling reaction of inactivated aryl chlorides with aryl
Grignard reagents
George Y. Li *
The DuPont Company, Central Research and Development Department, Experimental Station, PO Box 80328, Wilmington, DE 19880-0328, USA
Received 3 September 2001; accepted 18 September 2001
Abstract
Palladium(II) chlorides possessing phosphinous acid ligands have proved to be remarkably active and efficient catalysts for cross-
coupling reactions of inactivated aryl chlorides with aryl Grignard reagents (Kumadaꢀ
/
TamaoꢀCorriu reaction) at room
/
1
31
temperature to yield the corresponding biaryls with isolated product yields ranging from 51 to 99%. H- and P-NMR studies
argue that these phosphinous acid ligands in the complexes can be deprotonated to yield electron-rich anionic species, which is
anticipated not only to accelerate the rate-determining oxidative addition of aryl chlorides in the catalytic cycle, but also to stabilize
the transition-metal complexes. # 2002 Published by Elsevier Science B.V.
Keywords: [(t-Bu)
2
PÃ
/
OH)]
2
PdCl ; [(t-Bu)
2
2
PÃ
/
OH)PdCl
2
]
2
; Cross-coupling; Kumadaꢀ
/
TamaoꢀCorriu reaction
/
1
. Introduction
CarbonÃcarbon bond-forming reactions involving
stable phosphine oxides [R P(O)H] and phosphine
2
sulfides [R P(S)H] ligand precursors, for a variety of
2
/
transition-metal-catalyzed cross-coupling reactions of
inactivated aryl chlorides [8]. All these reactions are
aryl halides are important synthetic transformations in
synthetic chemistry [1], and the efficient cross-coupling
reactions of aryl halides and Grignard reagents repre-
sent versatile and powerful approaches for constructing
a diverse variety of biaryl compounds [2], which are
important industrial intermediates for photo-materials,
polymers, pharmaceuticals, agrochemicals, and homo-
geneous ligands. However, the lack of air-stable palla-
dium-catalysts for cross-coupling of more readily
available and less expensive aryl chlorides [3,4] with
aryl Grignard reagents, and the necessity for elevated
mediated by metalꢀ
phinothious acid compounds [9] which are generated via
tautomerization of R P(O)H or R P(S)H in the presence
/
phosphinous acid or metalꢀ
/
phos-
2
2
of transition metals. These air-stable complexes can be
deprotonated in the presence of base to generate anionic
species as catalysts for ClÃ
/
C bond activation of aryl
chlorides (Scheme 1).
Herein, we report our results on the use of isolated
air-stable palladium complexes as catalyst precursors for
the CÃ
/
C bond-forming reactions of aryl chlorides with
aryl Grignard reagents in high yields at ambient
reaction temperatures to activate CÃ
chlorides, prompted us to search for new, highly active,
and air-stable catalysts.
/Cl bond of aryl
temperature.
As part of our ongoing efforts to apply combinatorial
technologies for the discovery of new industrial homo-
2. Results and discussion
geneous catalysts [5ꢀ7], we reported the discovery of air-
/
The goal of this study was to employ new types of
anionic palladium(II) catalysts for cross-coupling of aryl
chlorides, to examine the scope, regiospecificity, cataly-
tic activity, and mechanism of these isolated, air-stable
*
Corresponding author. Present address: CombiPhos Catalysts,
Inc., PO Box 220, Princeton, NJ 08452-0220, USA. Fax: ꢁ1-908-281-
698.
E-mail address: george.y.li@combiphos.com (G.Y. Li).
9
0
palladiumꢀphosphinous acids-catalyzed cross-coupling
/
022-328X/02/$ - see front matter # 2002 Published by Elsevier Science B.V.
PII: S 0 0 2 2 - 3 2 8 X ( 0 2 ) 0 1 2 5 9 - 7

64
G.Y. Li / Journal of Organometallic Chemistry 653 (2002) 63ꢀ68
/
room temperature to yield the desired biaryls in high
isolated yields. Entries 1, 3, 4 and 5 illustrate that a
variety of electron-rich chloroanisoles could be coupled
with aryl Grignard reagents quantitatively. Entries 4
and 5 demonstrate that both more sterically demanding
and electron-rich substrate 3-chloroanisole was coupled
with aryl Grignard reagents to yield 3-(2,4,6-trimethyl-
phenyl)anisole and 3-(2-tolyl)anisole, respectively. En-
tries 6, 7 and 8 illustrate that Grignard reagents are
effective coupling groups with aryl chlorides yielding 2-
phenyltoluene and biphenyl.
Scheme 1.
reaction of aryl chlorides and aryl Grignard reagents.
To compare and contrast with the KumadaꢀTamaoꢀ
Corriu reaction of aryl chlorides mediated by nickelꢀ(t-
/
/
A number of aspects of the present palladiumꢀ
/
/
phosphinous acid catalysts are noteworthy and offer
both informative parallels and contrasts to the corre-
Bu) P [4], palladiumꢀ
/
imidazolium chlorides [3] and
phosphine oxides [8a], which are produced in-
3
nickelꢀ
/
sponding nickelꢀ
/
phosphine [4] and palladiumꢀ/imidazo-
situ via a reaction of nickel or palladium and ligands,
the present work focused on phosphinous acid ligand
variation while transition metals and reagents were held
constant, on catalytic regioselectivity, and on the factors
affecting reaction rate and rate-limiting oxidative addi-
tions.
lium chloride [3], as well as nickelꢀ
/
phosphinous acid
ligands [8a] in the cross-coupling of aryl chlorides with
aryl Grignard reagents. The present catalysts are cap-
able of employing a diverse variety of air-stable phos-
phine oxides [RR?P(O)H] as ligand precursors for Pd-
catalyzed cross-coupling reactions of aryl chlorides and
The ligand precursors used for cross-coupling reac-
tions were straightforwardly synthesized by reaction of
R PCl with H O in organic solvents [10], or by our
aryl Grignard reagents (Kumadaꢀ
/
TamaoꢀCorriu cou-
/
pling reaction) at room temperature, and all the
phosphine oxides can be easily synthesized via a
polymer-supported combinatorial approach [5,7], all
the cross-coupling results are comparable with those
2
2
previously reported polymer-supported approaches
Scheme 2) [5,7,8a].
(
from the corresponding Niꢀ
the same reaction conditions and from Niꢀ
salts [4]. Interestingly, and in marked contrast to the
Pdꢀimidazolium salt [3] for KumadaꢀTamaoꢀCorriu
/phosphinous acids [8a] at
/
imidazolium
/
/
/
cross-coupling of aryl chlorides, the present catalyst
systems showed the cross-coupling can be carried out at
room temperature in a low catalyst loading. It would
thus appear that the oxidative addition (rate-limiting
step) of aryl chlorides in the catalytic cycle is facilitated,
presumably due to anionic palladium-species produced
in the presence of a Grignard reagent (Scheme 3), which
are employed to form more reactant-like transition
states for such a rate-limiting process.
Scheme 2.
More importantly, from the standpoint of organic
synthesis, the direct use of air-stable POPd, POPd1 and
POPd2 as catalysts for cross-couplings of aryl chlorides
would be more practical owing to the difficulties in
generating in situ catalysts and in handling extremely
air-sensitive phosphine ligands [4].
The precatalysts were generated by treating PdCl2
with phosphine oxides [R P(O)H] in organic solvents
2
[
out in organic solvents (e.g. THF, Et O, dioxane) under
11]. The catalytic cross-coupling reactions were carried
2
anhydrous j anaerobic (catalyst loading: 0.5ꢀ
/
1.0 mol%).
Isolated yields in Table 1 refer to products isolated by
column chromatography. Known products were identi-
fied by comparison with literature data and/or with
those of authentic samples. New compounds were
3
1
With regard to a plausible mechanism, P-NMR
studies of the reaction of POPd with Et N in CDCl
3
3
solution argue that in the presence of bases, POPd is
subject to generate a chloro-bridged dinuclear species,
and yielding an electron-rich phosphine-containing
anionic complex [12], which is anticipated not only to
accelerate the rate-determining oxidative addition of
aryl chlorides in the catalytic cycle [13], but also to
1
13
characterized by 1-D and 2-D H/ C-NMR, HRMS,
or elemental analysis.
The results of Table 1 demonstrated that palladiu-
m(II) complexes of the type (R POH) PdCl (nꢂ1, 2;
/
2
n
m
mꢂ
/
1, 2) and {[R POꢀ ꢀ ꢀHꢀ ꢀ ꢀOPR ] PdCl} were cap-
2
2 2
2
able of catalyzing the cross-coupling reactions of a
variety of aryl chlorides and aryl Grignard reagents at
stabilize the transition metals via a OÃ
/
PÃ
/
M conjugation
(Scheme 4). Direct evidence for this pathway derives

G.Y. Li / Journal of Organometallic Chemistry 653 (2002) 63ꢀ
/68
65
Table 1
Palladium-catalyzed Kumadaꢀ
/
TamaoꢀCorriu cross-couplings of aryl chlorides
/
from the reaction of POPd with K CO in THF, which
2
new, simple, readily accessible, air-stable, and efficient
palladium(II) catalyst precursors for catalysis are cur-
rently under investigation.
3
generates an anionic dimer POPd1 [8c,8d].
3
. Conclusion
4. Experimental
In conclusion, we have shown for the first time that
air-stable palladium(II) complexes bearing phosphinous
acid ligands are ideal catalyst precursors for the activa-
4.1. General considerations
tion of CÃ
/
Cl bonds of inactivated aryl chlorides, and
that such processes can be incorporated into efficient
catalytic cycles for cross-coupling reactions of aryl
chlorides with aryl Grignard reagents. Of note is the
efficiency for inactivated aryl chlorides; and ready
accessibility for these catalyst precursors via polymer-
supported approaches. Additional applications of these
All reagents were used as supplied commercially
without further purification. Dihydrogen dichloro-
bis(di-tert-butylphosphinito-kP)palladate(2-)
Bu) POH) PdCl referred as POPd], and dihydrogen
di-m-chlorodichlorobis(di-tert-butylphosphinito-
kP)dipalladate(2-) {[(t-Bu) P(OH)PdCl referred as
[(t-
2
2
2
]
2 2
2
POPd2} are available exclusively from CombiPhos
Catalysts, Inc. Alternatively, they may be prepared
according to our reported procedures [8c,8d]. NMR
spectra were recorded on either a Nicolet NMC-300
1
13
wide-bore (FT, 300 MHz, H; 75 MHz, C; 121 MHz,
3
1
1
P), or GE QM-300 narrow-bore (FT, 500 MHz, H)
1
13
instrument. Chemical shifts (d) for H, C are refer-
enced to internal solvent resonances and reported
3
relative to SiMe4. P-NMR shifts are reported relative
1
to external phosphoric acid. Mass spectral data were
Scheme 3. Air-stable palladium complexes employed in Table 1.
Scheme 4.

66
G.Y. Li / Journal of Organometallic Chemistry 653 (2002) 63ꢀ68
/
obtained on a Kratos CONCEPT IH instrument at 70
eV.
ml of THF was refluxed under nitrogen condition
overnight. After the mixture was cooled to r.t., the
THF was removed under vacuum. The residue was
4
.2. Preparation of dihydrogen di-m-
chlorotetrakis(diphenylphosphinito-kP)dipalladate(2-)
14]
washed with Et O (5ꢃ
/
50 ml) and hexane (5ꢃ50 ml),
/
2
purified by column chromatography on silica gel to
afford 5.9 g (51% yield) of {[(i-Pr) POꢀ ꢀ ꢀHꢀ ꢀ ꢀOP(i-
[
2
1
95% pure by H-NMR and
Pr) ]PdCl} . It was ꢀ
/
2
2
1
MS. H-NMR (500 MHz, CDCl ): d 2.19 (m,
A solution of Pd(OAc) (5.0 g, 22.27 mmol), Ph PCl
2
GCꢀ
/
2
3
1
4H), 1.36 (m, 12H), 1.22 (m, 12H) ppm, C-NMR (126
3
(
10.0 g, 45.3 mmol) and H O (0.816 g, 45.3 mmol) in 100
2
3
1
ml of 1,4-dioxane was refluxed under nitrogen condition
overnight. After the mixture was cooled to room
temperature (r.t.), the dioxane was removed under
MHz, CDCl ): d 31.2, 19.5, 17.4 ppm. P-NMR (202
3
1
MHz, CDCl ): d 118.3 ppm. H-coupled P-NMR (202
31
3
MHz, CDCl ): d 118.3 (s) ppm. Anal. Calc. for
3
vacuum. The residue was washed with Et O (5ꢃ
/
50
50 ml), purified by column chro-
matography on silica gel to afford 10.0 g (82% yield) of
[(Ph) POꢀ ꢀ ꢀHꢀ ꢀ ꢀOP(Ph) ]PdCl} . It was ꢀ95% pure
MS. H-NMR (300 MHz,
CDCl ): d 7.60 (m, 16H), 7.40 (m, 8H), 7.27 (m, 16H)
C H O Cl P Pd : C, 35.22; H, 7.14; Cl, 8.66; P,
2
2
24 58
4
2
4
ml) and hexane (5ꢃ
/
15.14. Found: C, 35.40; H, 7.24; Cl, 8.98; P, 15.24%.
{
/
4.5. Synthesis of 4-(2-tolyl)anisole
2
2
2
1
l
by H-NMR and GCꢀ
/
In the drybox, 25.0 mg (0.05 mm) of POPd, 1.43 g
(10.0 mm) of 4-chloroanisol and 10.0 ml of THF were
loaded into a reactor (50 ml) equipped with a magnetic
stir bar. The resulting mixture was stirred when addition
of 15 ml (15.0 mm, 1.0 M in THF) of O-tolylmagnesium
chloride at r.t. over a period of 5 min. The resulting
mixture was stirred at r.t. over 4 h before the reaction
3
1
3
ppm. C-NMR (76 MHz, CDCl ): d 135.3 (d, Jꢂ
/
71.3
5.96
3
Hz), 132.0 (t, Jꢂ
/
6.08 Hz), 130.9 (s), 127.9 (t, Jꢂ
/
3
l
Hz) ppm. P-NMR (121 MHz, CDCl ): d 79.5 ppm.
1
3
31
H-coupled P-NMR (121 MHz, CDCl ): d 79.5 (s)
3
ppm. Anal. Calc. for C H O Cl P Pd : C, 52.87; H,
2
4
8
42
4
2
4
3
6
.88; Cl, 6.50; P, 11.36. Found: C, 53.30; H, 3.68; Cl,
.41; P, 10.76%. The crystallographic sample was
was quenched with 10.0 ml of H O, and the mixture was
2
obtained by slow recrystallization from a mixture of
CH Cl and hexane [8c,8d].
diluted with 300 ml of Et O. After separation of organic
2
and aqueous phases, the organic phase was washed with
50 ml of H O, and 50 ml of brine, then dried over
MgSO , filtered and concentrated by rotary evapora-
2
2
2
4.3. Preparation of dihydrogen di-m-
chlorotetrakis(dicyclohexylphosphinito-
kP)dipalladate(2-)
4
tion. The crude product was purified by column
chromatography on silica gel (100: 1-hexane: methyl t-
butyl ether) to afford 1.72 g (87% yield) of 4-(o-
1
95% pure by H-NMR and
A solution of PdCl (1.90 g, 10.74 mmol), Cy PCl (5.0
2
tolyl)anisole. It was ꢀ
/
2
1
g, 21.48 mmol) and H O (1.0 g, 55.6 mmol) in 100 ml of
2
GCꢀ
/
MS. H-NMR (300 MHz, CDCl ): d 7.33ꢀ7.00
/
3
1
3
(m, 8H), 3.91 (s, 3H), 2.34 (s, 3H) ppm. C-NMR (75
THF was refluxed under nitrogen condition overnight.
After the mixture was cooled to r.t., the THF was
removed under vacuum. The residue was washed with
MHz, CDCl ): d 158.5, 141.5, 135.3, 134.3, 130.2, 130.1,
3
129.8, 126.8, 125.7, 113.4, 55.0, 20.4 ppm. HRMS Calc.
For C H O: 199.1122. Found: 199.1121. Anal Calc.
Et O (5ꢃ
/
50 ml) and hexane (5ꢃ
/
50 ml), purified by
column chromatography on silica gel to afford 5.3 g
2
14 14
for C H O: C, 84.81; H, 7.12. Found: C, 84.65; H,
1
4
14
(
87% yield) of {[Cy POꢀ ꢀ ꢀHꢀ ꢀ ꢀOPCy ]PdCl} . It was ꢀ
/
6.98%.
2
2
2
1
1
9
5% pure by H-NMR and GCꢀ
/
MS. H-NMR (500
3.44 (m, 8H),
1.15 (m, 34H) ppm. C-NMR (76 MHz, CDCl3):
d 40.58 (d, Jꢂ28.27 Hz), 40.46 (d, Jꢂ38.88 Hz), 40.45
d, Jꢂ28.28 Hz), 29.0, 27.6, 26.8 (dt, Jꢂ49.69 Hz, Jꢂ
.49 Hz) ppm. P-NMR (202 MHz, CDCl ): d 113.5
MHz, CDCl ): d 3.61 (m, 4H), 3.56ꢀ
7
/
4.6. Synthesis of 2-phenyltoluene
3
1
3
2.31ꢀ
/
/
/
In the drybox, 50.0 mg (0.10 mm) of POPd, 1.13 g
(10.0 mm) of chlorobenzene and 10.0 ml of THF were
loaded into a reactor (50 ml) equipped with a magnetic
stir bar. The resulting mixture was stirred when addition
of 15 ml (15.0 mm, 1.0 M in THF) of O-tolylmagnesium
chloride at r.t. over a period of 5 min. The resulting
mixture was stirred at r.t. over 4 h before the reaction
(
7
/
/
/
3
1
3
1
31
ppm. H-coupled P-NMR (202 MHz, CDCl ): d 113.5
3
(
H, 7.97; Cl, 6.23; P, 10.88. Found: C, 50.70; H, 8.10; Cl,
6
s) ppm. Anal. Calc. for C H O Cl P ,Pd : C, 50.62;
48 90 4 2 4 2
.25; P, 10.99%.
was quenched with 10.0 ml of H O, and the mixture was
2
4
.4. Preparation of dihydrogen di-m-chlorotetrakis(di-
iso-propylphosphinito-kP)dipalladate(2-)
diluted with 300 ml of Et O. After separation of organic
2
and aqueous phases, the organic phase was washed with
50 ml of H O, and 50 ml of brine, then dried over
MgSO , filtered and concentrated by rotary evapora-
2
A solution of PdCl (5.0 g, 28.2 mmol), (i-Pr) PCl
2
2
4
(
8.97 g, 56.4 mmol) and H O (1.2 g, 66.7 mmol) in 100
2
tion. The crude product was purified by column

G.Y. Li / Journal of Organometallic Chemistry 653 (2002) 63ꢀ
/68
67
chromatography on silica gel to afford 1.66 g (99%
1
95% pure by H-
10.0 ml of H O, and the mixture was diluted with 300 ml
2
yield) of 2-phenyltoluene. It was ꢀ
/
of Et O. After separation of organic and aqueous
2
1
NMR and GCꢀ
.6ꢀ7.47 (m, 9H), 2.50 (s, 3H) ppm. C-NMR (125
MHz, CDCl ): d 142.0, 141.9, 135.2, 130.3, 129.7, 129.1,
/
MS. H-NMR (500 MHz, CDCl ): d
phases, the organic phase was washed with 50 ml of
H O, and 50 ml of brine, then dried over MgSO ,
3
1
3
7
/
2
4
filtered and concentrated by rotary evaporation. The
crude product was purified by column chromatography
on silica gel to afford 1.1 g (60% yield) of 2-phenylto-
luene.
3
1
C H : 169.1017. Found: 169.1016. Anal Calc. for
28.0, 127.2, 126.7, 125.7, 20.4 ppm. HRMS Calc. for
1
3
12
C H : C, 92.81; H, 7.19. Found: C, 92.60; H, 7.08%.
3
1
12
4
.7. Synthesis of 3-(2-tolyl)anisole [15]
4.10. Synthesis of biphenyl
In the drybox, 68.0 mg (0.10 mm) of POPd2, 1.43 g
10.0 mm) of 3-chloroanisol and 10.0 ml of THF were
In the drybox, 82.0 mg (0.10 mm) of {[(i-
(
Pr) POꢀ ꢀ ꢀHꢀ ꢀ ꢀOP(i-Pr) ]PdCl} and 1.13 g (10.0 mm)
2
2
2
loaded into a reactor (50 ml) equipped with a magnetic
stir bar. The resulting mixture was stirred when addition
of 15 ml (15.0 mm, 1.0 M in THF) of O-tolylmagnesium
chloride at r.t. over a period of 5 min. The resulting
mixture was stirred at r.t. over 4 h before the reaction
of chlorobenzene were loaded into a reactor (20 ml)
equipped with a magnetic stir bar. The resulting mixture
was stirred when addition of 7.5 ml (15.0 mm, 2.0 M in
THF) of phenylmagnesium chloride at r.t. over a period
of 5 min. The resulting mixture was stirred at r.t. over 4
was quenched with 10.0 ml of H O, and the mixture was
2
h before the reaction was quenched with 10.0 ml of H O,
2
diluted with 300 ml of Et O. After separation of organic
2
and the mixture was diluted with 300 ml of hexane.
After separation of organic and aqueous phases, the
organic phase was washed with 70 ml of H O, and 100
and aqueous phases, the organic phase was washed with
5
MgSO , filtered and concentrated by rotary evapora-
0 ml of H O, and 50 ml of brine, then dried over
2
2
4
ml of brine, then dried over MgSO , filtered and
4
tion. The crude product was purified by column
chromatography on silica gel to afford 1.75 g (88%
yield) of 3-(o-tolyl) anisole.
concentrated by rotary evaporation. The crude product
was purified by column chromatography on silica gel to
afford 1.44 g (93% yield) of biphenyl. It was ꢀ
/
95% pure
MS. H-NMR (500 MHz,
7.75 Hz, 4H), 7.60 (t, Jꢂ7.65
7.38 Hz, 2H) ppm. C-NMR (125
1
1
by H-NMR and GCꢀ
/
4
.8. Synthesis of 2-phenyltoluene
CDCl ): d 7.77 (d, Jꢂ
Hz, 4H), 7.50 (t, Jꢂ
/
/
3
1
3
/
In the drybox, 109 mg (0.10 mm) of
MHz, CDCl ): d 141.2, 128.7, 127.2, 127.1 ppm.
HRMS: Calc. for C H : 154.0783. Found: 154.0785%.
3
{
[(Ph) POꢀ ꢀ ꢀHꢀ ꢀ ꢀOP(Ph) ]PdCl} , 1.13 g (10.0 mm) of
2
2
2
1
2
10
chlorobenzene and 10.0 ml of THF were loaded into a
reactor (50 ml) equipped with a magnetic stir bar. The
resulting mixture was stirred when addition of 15 ml
4.11. Synthesis of 4-phenylanisole
(
15.0 mm, 1.0 M in THF) of O-tolylmagnesium chloride
at r.t. over a period of 5 min. The resulting mixture was
stirred at r.t. over 14 h before the reaction was quenched
with 10.0 ml of H O, and the mixture was diluted with
In the drybox, 66.6 mg (0.050 mm) of POPd1, 1.43 g
(10.0 mm) of 4-chloroanisol was loaded into a reactor
(50 ml) equipped with a magnetic stir bar. The resulting
mixture was stirred when addition of 7.5 ml (15.0 mm,
2.0 M in THF) of phenylmagnesium chloride at r.t. over
a period of 5 min. The resulting mixture was stirred at
r.t. over 4 h before the reaction was quenched with 10.0
2
300 ml of Et O. After separation of organic and aqueous
2
phases, the organic phase was washed with 50 ml of
H O, and 50 ml of brine, then dried over MgSO ,
2
4
filtered and concentrated by rotary evaporation. The
crude product was purified by column chromatography
on silica gel to afford 1.52 g (90% yield) of 2-
phenyltoluene.
ml of H O, and the mixture was diluted with 300 ml of
2
Et O. After separation of organic and aqueous phases,
2
the organic phase was washed with 50 ml of H O, and
2
50 ml of brine, then dried over MgSO , filtered and
concentrated by rotary evaporation. The crude product
4
4
.9. Synthesis of 2-phenyltoluene
was purified by column chromatography on silica gel to
In the drybox, 114 mg (0.10 mm) of {[Cy2-
afford 1.05 g (57% yield) of 4-phenylanisole. It was ꢀ
/
1
1
MS. H-NMR (500
POꢀ ꢀ ꢀHꢀ ꢀ ꢀOPCy ]PdCl} 1.13 g (10.0 mm) of chloro-
95% pure by H-NMR and GCꢀ
/
2
2,
benzene and 10.0 ml of THF were loaded into a reactor
50 ml) equipped with a magnetic stir bar. The resulting
mixture was stirred when addition of 15 ml (15.0 mm,
.0 M in THF) of O-tolylmagnesium chloride at r.t.
MHz, CDCl ): d 7.45 (m, 4H), 7.32 (m, 2H), 7.21 (m,
1
3
3
(
1H), 6.88 (d, Jꢂ8.72 Hz, 2H), 3.74 (s, 3H) ppm. C-
/
NMR (125 MHz, CDCl ): d 159.2, 140.8, 133.8, 128.7,
3
1
128.1, 126.7, 126.6, 114.2, 55.3 ppm. Anal. Calc. for
C H O: C, 84.75; H, 6.57; O, 8.68. Found: C, 84.81; H,
6.65; O, 8.62%.
over a period of 5 min. The resulting mixture was stirred
at r.t. over 14 h before the reaction was quenched with
1
3
12

68
G.Y. Li / Journal of Organometallic Chemistry 653 (2002) 63ꢀ68
/
[
5] (a) For combinatorial approaches to the synthesis of phosphine
ligands, see: G.Y. Li, P.J. Fagan, P.L. Watson, Angew. Chem.
Int. Ed. Engl. 40 (2001) 1106ꢀ1109;
b) G.Y. Li (E.I. Du Pont de Nemours and Company, USA), US
4
.12. Synthesis of 3-(2,4,6-trimethylphenyl)anisole
/
In the drybox, 47.0 mg (0.0505 mm) of POPd1 and
.86 g (20.0 mm) of 3-chlorideanisole were loaded into a
(
2
patent application, No. 60/197,031, Case Number: BC 1048 US
reactor (50 ml) equipped with a magnetic stir bar. The
resulting mixture was stirred when addition of 30 ml
PRV, (2000);
(c) P.J. Pagan, G.Y. Li, Z. Guan, L. Wang, 2000, US Patent
6,137,012;
(
30.0 mm, 1.0 M in THF) of 2-mesitylmagnesium
(
d) P.J. Pagan, G.Y. Li, PCT Int. Appl WO 2000021663 A2
0000420, 169 pp. APPLICATION:WO 1999-US23509 19991013
6] For combinatorial approaches to the synthesis of bisphosphine-
bromide at r.t. over a period of 5 min. The resulting
mixture was stirred at r.t. over 14 h before the reaction
was quenched with 50.0 ml of H O, and the mixture was
2
[
2
related ligands, see: G.Y. Li, J. Comb. Chem. 2002, in press.
diluted with 300 ml of Et O. After separation of organic
2
[7] For combinatorial approaches to the synthesis of phosphorous-
heteroatom-containing ligands, see: G.Y. Li, J. Am. Chem. Soc.
2002, in press.
and aqueous phases, the organic phase was washed with
1
MgSO , filtered and concentrated by rotary evapora-
00 ml of H O, and 100 ml of brine, then dried over
2
[8] (a) For using phosphine oxides and phosphine sulfides as ligands
4
for homogeneous catalysis, see: G.Y. Li, Angew. Chem. Int. Ed.
tion. The crude product was purified by column
chromatography on silica gel (100: 1-hexane: Acetate)
to afford 2.3 g (51% yield) of the title compound. It was
4
0 (2001) 1513ꢀ
b) G.Y. Li, G. Zheng, A.F. Noonan, J. Org. Chem. 66 (2001)
677ꢀ8681;
(c) G.Y. Li, W.J. Marshall, Organometallics 21 (2001) 590ꢀ
/
1516;
(
8
/
1
1
ꢀ
/
95% pure by H-NMR and GCꢀ
/
MS. H-NMR (300
7.08
6.95 (m, 2H), 4.00 (s, 3H), 2.56 (s, 3H),
/591;
MHz, CDCl ): d 7.54 (m, 1H), 7.17 (s, 2H), 7.09ꢀ
/
(d) G.Y. Li (E.I. DuPont de Nemours and Company, USA), US
3
Patent 6,124,462, 2000;
(
m, 1H), 6.98ꢀ
/
1
3
(e) G.Y. Li (E.I. Du Pont de Nemours and Company, USA), US
Patent 6,291,722 B1, 2001;
2
1
1
2
.28 (s, 6H) ppm. C-NMR (75 MHz, CDCl ): d 159.6,
3
42.5, 138.9, 136.4, 135.7, 129.3, 128.0, 121.6, 114.8,
11.9, 54.9, 20.9, 20.5 ppm. HRMS: Calc. for C H O:
27.1436. Found: 227.1434%.
(
f) G.Y. Li (E.I. Du Pont de Nemours and Company, USA), US
1
6
18
Patent Application No: 60/274,530, Case Number: BC1029 US
NA PRV (2001).
[
9] (a) For metalꢀ
C.J. Cobley, M. vanden Heuvel, A. Abbadi, J.G. de Vries,
Tetrahedron Lett. 2467 41 (2000) 2467ꢀ2470;
b) T. Ghaffar, A.W. Parkins, Tetrahedron Lett. 36 (1995) 8657ꢀ
/
phosphinous acid complexes, for examples, see:
/
Acknowledgements
(
/
8
660; UK patent Application 9506389.7;
The authors wish to thank Dr. Patrick Y.S. Lam and
Dr. Rafael Shapiro for helpful discussions and sugges-
tions.
(
c) J.R. Goerlich, A. Fischer, P.G. Jones, R.Z. Schmutzler, B
Naturforsch, Chem. Sci. 49 (1994) 801ꢀ811;
(d) L. Heuer, P.G. Jones, R. Schmutzler, New J. Chem. 14 (1990)
91ꢀ900;
e) A.M. Arif, T.A. Bright, R.A. Jones, J. Coord. Chem. 16 (1987)
5ꢀ50
10] (a) V.L. Foss, P.L. Kukhmisterov, P.L. Lutsenko, I.F. Mosk,
USSR. Zh. Obshch. Khim. 52 (5) (1982) 1054ꢀ1062;
b) E. Lindner, A. Nothdurft, Z. Anorg. Allg. Chem. 579 (1989)
00ꢀ204.
11] (t-Bu) POH)
Bu) ]PdCl}
/
8
/
(
4
/
References
[
[
[
[
/
[
1] (a) For general references, see: E.-i. Negishi, F. Liu, in: F.
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(
2
/
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/
/
H
/
ꢀ ꢀ ꢀ
/
OP(t-
(
2
2
(POPd1) and [(t-Bu)
2
P(OH)PdCl ] (POPd2) are
2 2
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/
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(
(
/
12] A reaction of (t-Bu)
2
POH)
2
PdCl
2
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3
3
at room
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/
31
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[
(
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W.A. Herrmann, Angew. Chem. Int. Ed. 39 (2000) 1602ꢀ1604.
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13] The low catalytic reactivity of aryl chlorides in cross-coupling
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(
1
[
[
/
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/
H. Alper, Chem. Rev. 94 (1994) 1047ꢀ
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/
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/