Application of palladium-catalyzed Pd-aryl/P-aryl exchanges: Preparation of functionalized aryl phosphines by phosphination of aryl bromides using triarylphosphines

Article abstract of DOI:10.1016/j.tet.2004.04.085

Palladium-catalyzed Pd-aryl/P-aryl interchange reaction was applied in the synthesis of various functionalized arylphosphines. This phosphination used inexpensive, readily available and air stable triarylphosphines as the phosphinating agents. Broad functional groups were compatible including keto, aldehyde, ester, nitrile, ether, chloride, pyridyl and thiophenyl groups. Halides were found to be good promoter for the rates and yields of the reaction.

Full text of DOI:10.1016/j.tet.2004.04.085

Tetrahedron 60 (2004) 5635–5645
Application of palladium-catalyzed Pd–aryl/P–aryl exchanges:
preparation of functionalized aryl phosphines by phosphination of
aryl bromides using triarylphosphines
*
Fuk Yee Kwong, Chi Wai Lai, Michael Yu and Kin Shing Chan
†
Department of Chemistry, Open Laboratory of Chirotechnology of the Institute of Molecular Technology for Drug Discovery and Synthesis,
The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, People’s Republic of China
Received 31 January 2004; revised 15 April 2004; accepted 19 April 2004
Abstract—Palladium-catalyzed Pd–aryl/P–aryl interchange reaction was applied in the synthesis of various functionalized arylphosphines.
This phosphination used inexpensive, readily available and air stable triarylphosphines as the phosphinating agents. Broad functional groups
were compatible including keto, aldehyde, ester, nitrile, ether, chloride, pyridyl and thiophenyl groups. Halides were found to be good
promoter for the rates and yields of the reaction.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
desired polymer may be altered, possibly resulting in poorer
1
properties.
2
Cross-coupling reactions are important in organic synthesis,
especially in pharmaceutical areas. Palladium-catalyzed
coupling methodologies are powerful protocols for carbon–
1
4
15
16
Cheng, Novak and Grushin have demonstrated this
aryl exchange reaction is an equilibrium process. The
equilibrium is possibly a fine balance of the electronic and
steric nature of the phopshine ligands. Mechanistic studies
reveal that electron rich arylphosphines facilitate the
1
carbon and carbon–heteroatom bond formation. However,
some of the undesirable side reactions such as Pd–aryl/
P–aryl interchanges were observed when arylphosphine
ligands were used (Eq. 1).
1
5
Pd–aryl/P–aryl interchange reactions, as the electron-
donating group may stabilize the developing positive charge
from the phosphonium salt intermediate (see Scheme 2,
proposed mechanism). From these results, we utilized the
aryl–aryl exchange reactions in the preparation of func-
ð1Þ
tionalized aryldiphenylphosphine (ArPPh ) from aryl
2
bromides and triphenylphosphine in the presence of
palladium catalyst (Eq. 2).
The Pd–aryl/P–aryl interchange in forming the scrambled
side reaction products have been observed in Suzuki–
2
3
4,5
Miyaura coupling, Stille coupling, Heck reaction,
6
7
8
9
amination, amidation, ketone-arylation, cyanation, and
1
ð2Þ
0,11
12
C–S bond formation reactions,
polymer synthesis,
1
3
and etc. (Scheme 1). Consequently, the yields of the
reactions suffer and the purification of products becomes
more difficult. The unwanted coupled products usually are
obtained from 4 to 58% yield in those couplings (Scheme 1).
Furthermore, in polymer synthesis, the architecture of the
Synthesis of functionalized aromatic phosphines for the
application in fine-tuning catalysis is highly desirable.
However synthetic methods available are limited in scope.
Traditional methods for the preparation of aromatic
phosphines can be classified into two major categories.
One method involves the reaction of aryl Grignard or
organolithium reagents with chlorophosphines, and is
Keywords:
Triarylphosphine; Cross-coupling; Catalysis.
Phosphination;
Palladium;
Triphenylphosphine;
*
Corresponding author. Tel.: þ852-2609-6376; fax: þ852-2603-5057;
e-mail address: ksc@cuhk.edu.hk
1
7
intolerant to a wide variety of functional groups. The
second method is the transition metal-catalyzed phosphina-
tion. Both nickel- and palladium-catalyzed phosphination of
†
A University Grants Committee, Area of Excellence Scheme (Hong
Kong).
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.04.085

5636
F. Y. Kwong et al. / Tetrahedron 60 (2004) 5635–5645
Scheme 1. Product scrambling in palladium-catalyzed cross-coupling reactions.
8,19
1
aryl triflates/halides using diphenylphosphine
0
(Ph PH)
or chlorodiphenylphosphine (Ph PCl) were reported
successful catalyzed phosphination with triarylphosphines
27
has prompted us to extend the method to aryl halides.
2
2
2
2
1
recently. The pioneering work of Stille using Pd/
TMSPPh system showed C–P bond formation from aryl
4-Bromoacetophenone was therefore chosen as the proto-
typical substrate for screening the optimal reaction
conditions. Both palladium(II) acetate and tetrakis(tri-
phenylphosphine) palladium(0) complexes catalyzed the
phosphination. A lower yield of the reaction was observed
when Pd (dba) complex was used, since dba (trans-
2
2
2
iodides. An alternative two-steps phosphine synthesis
using Pd/Ph P(O)H protocol requires subsequent
2
2
3
reduction. Recently, Lipshutz and co-workers have
reported attractive C–P coupling method from aryl
2
3
2
4
sulfonates using Pd/phosphine–borane system. In the
meanwhile, both Buchwald and Venkataraman groups
disclosed an inexpensive copper-catalyzed phosphination
dibenzylidieneacetone) ligand, has similar chromatographic
behavior with the desired products and the purification
procedure became more difficult. Therefore, palladium(II)
acetate catalyst was preferred. The optimal amounts of
triphenylphosphine added to the reaction were found to be
2
5
of aryl iodides. Herein, we report the palladium-catalyzed
phosphination of functionalized aryl bromides using readily
available triarylphosphines as the phosphinating agents to
2
7
2.3–2.5 equiv. with respect to aryl bromide. The opti-
mized reaction conditions were then applied to the synthesis
of other functionalized aryl phosphines (Table 1 and Eq. 3).
2
6
synthesize functionalized aryl phosphines.
2
. Results and discussion
4-Bromobenzaldehyde was directly phosphinated by tri-
phenylphosphine to form 4-(diphenylphosphino)benzalde-
hyde (Table 1, entry 1). In contrast, the previous preparation
Our initial discovery that pyridyl aryl triflates underwent

F. Y. Kwong et al. / Tetrahedron 60 (2004) 5635–5645
5637
Scheme 2. A plausible mechanism for palladium-catalyzed phosphination with added iodides.
3
2
of this phosphine, which finds many applications for water-
2
therefore very facile. ortho-Substituted substrates such as
2-bromoanisole and 2-bromotoluene were found to be ineffec-
tive. These starting materials were recovered almost quanti-
tatively after the reaction was heated for 72 h at 110 8C.
8
29
soluble polymers and porphyrins, involved a muti-step
synthesis requiring protection/deprotection of the aldehyde
3
0
group. Other functional groups, such as ester, nitrile, keto,
ether and chloride are tolerant to this phosphination reaction
(
Table 1, entries 2–6). In contrast, previous syntheses of
ester and nitrile containing phosphines required a long
Other triarylphoshphines were found to be efficient
diarylphosphinating agents for palladium catalyzed phos-
phination of aryl bromides (Table 2 and Eq. 5). The
p-bromoacetophenone was diarylphosphinated by trixylyl-
phosphine, tri(p-methoxyphenyl)phosphine and tri(p-tolyl)-
phosphine to yield the corresponding aromatic phosphines
in moderate yields with similar rate (Table 2, entries 1–3).
Sterically hindered tri(o-tolyl)phosphine did not react at all
(Table 2, entry 4). These examples demonstrate the
generality for diarylphosphination to synthesize various
sterically unhindered aryl phosphines.
3
1
synthetic pathway. Heterocyclic substrates, 3-bromopyri-
dine and 2-bromothiophene were found to be compatible in
this reaction (Table 1, entries 11–12).
Similar rates of reaction were observed for electronically
different non-coordinating aryl bromides. The rate of the
reaction of coordinating substrates, which contain ester,
aldehyde, nitrile, pyridyl and thiophenyl groups required a
longer reaction time (Table 1, entries 1, 3, 4, 11 and 12).
Presumably strongly coordinating substrates rendered the
catalyst complex coordinatively saturated and hence
reduced the catalytic efficiency.
A user-friendly, economically attractive and environmen-
tally benign phosphination was successfully carried out in
3
3
solvent-free conditions (Table 3). No significant elec-
tronic effect was observed in the solvent-free phosphination
since both electron-withdrawing and donating substrates
exhibited similar reaction rates (Table 3). ortho-Substituted
aryl bromides still did not react in solvent-free conditions
even at elevated temperature at 140 8C. The rates of the
reactions in solvent-free conditions were slower than those
in DMF. Presumably, the high viscosity of the reaction
ð4Þ
Some limitations of the substrates used in the palladium-
catalyzed phosphination reaction exist. 4-Nitrobromoben-
zene was found to react quickly within 12 h at 110 8C to
give no desired phosphinated-product but the 4-bromoani-
line in 58% yield (Eq. 4). Reduction of the nitro-group was
mixture was responsible. As Ph P melts at 79 8C, at the
3
reaction temperature of 110 8C, triphenylphosphine
behaved as the solvent, ligand and phosphinating agent.

5638
F. Y. Kwong et al. / Tetrahedron 60 (2004) 5635–5645
a
Table 1. Palladium-catalyzed phosphination of aryl bromides with triphenylphosphine
ð3Þ
b
Entry
1
Substrate
Product
Time (h)
64
% Yield
32
40
1
2
2
3
20
36
30
3
4
5
6
7
8
4
5
6
7
8
48
24
20
26
19
36
27
c
51
58
59
c
c
9
18
18
38
9
c
51
10
1
0
1
1
2
72
48
25
1
1
2
c
54
1
1
a
b
c
Reaction conditions: ArBr (1.0 mmol), Ph
Isolated yield.
GC yield in average of 2 runs.
3 2
P (2.3–2.5 mmol), Pd(OAc) (10 mol%) in DMF (4.0 mL) at 110–115 8C under nitrogen atmosphere.
Halides have been discovered to be promoters in many
transition metal-catalyzed processes and have become an
(Table 4). We found that the addition of 2.5 equiv. of NaI to
the reaction mixture did enhance the yield. The optimal
loading of NaI added was found to be around 5 equiv.
(Table 4). A higher loading of 10 equiv. of NaI gave a lower
yield of the product.
3
4
important aspect of catalysis optimization. To further
optimize the phosphination, we had investigated the effect
of halides and other anions in palladium-catalyzed phos-
phination of aryl bromides. Sodium iodide was used as the
prototypical salt to examine the salt-effect in this reaction
Other salts were also examined (Table 5). All halides gave

F. Y. Kwong et al. / Tetrahedron 60 (2004) 5635–5645
5639
a
Table 2. Palladium-catalyzed phosphination of 4-bromoacetophenone with triarylphosphines
ð5Þ
b
Entry
PAr
3
Product
Time (h)
% Yield
1
14
33
39
34
33
2
15
32
3
16
34
c
4
72
No rxn.
a
3 2
Reaction conditions: 4-bromoacetophenone (1.0 mmol), Ar P (2.3 mmol), Pd(OAc) (0.1 mmol, 10 mol%) in DMF (4.0 mL) at 110–115 8C under nitrogen
atmosphere.
Isolated yield.
Starting material was recovered.
b
c
better yields or faster rate of the reaction (Table 5, entry 1
vs. 2–5, 8–10). Among the halides, sodium salts exhibited
an equal or better promoting effect than potassium salts
for oxidative addition of carbon–halogen bond with
palladium catalyst. The possibility of converting aryl
bromides into aryl iodides by the addition of NaI was
supported by the observation of a trace amount of
4-iodoacetophenone generated during the course of the
phosphination of 4-bromoacetophenone by GC–MS analy-
sis (Eq. 7 and Scheme 2).
(
Et N) salts showed faster rate of reaction and higher yield of
Table 5, entries 3–5, 8–9). Iodide (MI, M¼Li, Na, K,
4
the product (Table 5, entries 2, 3, 8, 10). Alkali metal iodide
generally gave higher yields of reaction compared with
ammonium salts (Table 5, entries 1–2, 8 vs. 10). The best
result was found to be with the addition of 5 equiv. of NaI,
with the isolated yield of 4-(diphenylphosphino)aceto-
phenone obtained in 60%. Non-halide salts such as,
NaBF , NaPF and NH PF were found to be inferior
ð7Þ
ð8Þ
4
6
4
6
(
Table 5, entries 6, 7, 11).
The metal halides likely play several roles in the
phosphination. Firstly, the addition of salts to the reaction
increased the solvent polarity in the bulk environment,
which favors the oxidative addition and formation of
phosphonium salt intermediate (Scheme 2). Secondly, the
iodide salt may assist the halide exchange for aryl bromide
The more reactive 4-iodoacetophenone likely undergoes
fast oxidative addition with palladium catalyst in the
3
5
to aryl iodide, and hence provide a lower energy barrier

5640
F. Y. Kwong et al. / Tetrahedron 60 (2004) 5635–5645
a
Table 3. Solvent-free palladium-catalyzed phosphination of aryl bromides
b
Entry
1
Substrate
Product
Time (h)
1.5
% Yield
44
2
2
2.5
40
3
1
4
5
3
4
5
2.5
2.5
1.0
40
38
33
6
7
2.5
34
1
7
c
c
7
7
No rxn.
8
No rxn.
a
Reaction conditions: ArBr (1.0 mmol), Ph
Isolated yield.
Reaction temperature (140 8C).
3 2
P (2.3 mmol), and Pd(OAc) (0.1 mmol, 10 mol%) at 110–115 8C under nitrogen atmosphere.
b
c
catalytic cycles (Scheme 2). Indeed, 4-iodoacetophenone
reacted about three times faster than 4-bromoacetophenone
the concentration of coordinatively unsaturated palladium
species would increase. Pd–aryl/P–aryl exchanges would
be more facile as reported by Grushin on the addition step.
1
6
(
Eq. 8). Similar metal iodide acceleration phenomenon in
36
the cross-coupling reactions have been observed. More-
over, as iodide anion is less coordinating, therefore it
dissociates more rapidly than bromides and chlorides, and
Hence a faster rate of reaction was observed (Table 5,
entries 2, 3, 8, 10). The possibility of iodide anion in
forming a new pentacoordinated anionic palladium
3
4
3
7
species, which facilitates the subsequent reductive
elimination, could not be excluded.
Table 4. Salt loading in palladium-catalyzed phosphination
Scheme 2 illustrates a plausible mechanism for the reaction
involving Pd(0)/Pd(II) cycles. Palladium(II) acetate is in
situ reduced by triphenylphosphine to form acetate ligated
2
38,39
complex A, PdL (OAc) (L¼triphenylphosphine).
2
This active anionic palladium complex A then undergoes
oxidative addition with an aryl bromide to afford palladium
complex B (Scheme 2). Halide exchange by the addition
of iodide ion (from NaI or KI) generated complexes C
Entry
NaI (equiv).
% GC yield
4
0
1
2
3
4
0
2.5
5
44
56
68
56
37
and D. As we have observed that a trace amount of
4
reaction by GC–MS analysis, the ligand substitution
-iodoacetophenone formed during the course of the
4
10
1

F. Y. Kwong et al. / Tetrahedron 60 (2004) 5635–5645
5641
a
0
addition by carbon–phosphorus bond activation of the
Table 5. Salt effects in palladium-catalyzed phosphination of aryl bromide
The anionic palladium complex A or A undergoes oxidative
phosphonium salt E to generate the coordinated ArPPh Pd-
2
4
4,45
ð6Þ
complex (Scheme 2).
Finally, ligand substitution by
triphenylphosphine to Pd(II) complex F gives ArPPh and
2
Pd–phenyl complex G. The PdL2I2 species is regenerated
by reductive elimination of triphenylphosphine and Pd
bound phenyl group to yield the tetraphenylphosphonium
iodide co-product (Scheme 2). The formation of tetra-
b
Entry
Additive
Time (h)
% Yield
c
1
2
3
4
5
6
7
8
9
/
LiI
NaI
NaBr
NaCl
20
6
40
51
3
1
phenylphosphonium co-product was detected by P NMR
46
c
20
23
23
22
20
10
10
2
68 (60)
(
equivalents of PPh were required. The first one serves as
d¼24.0 ppm) in the reaction mixture. Therefore, two
65
51
34
0
67
40
49
0
3
the diphenylphosphinating agent and the second one yields
the phosphonium salt co-product.
NaBF
4
NaPF
KI
6
KBr
The iodide promoting effect in the phosphination was found
to be general for aryl bromides and the results are listed in
Table 6. Both the rates and about 10–20% increase in
product yields were observed.
1
1
0
1
Et
NH
4
NI
PF
4
6
20
a
Reaction conditions: ArBr (1.0 mmol), Ph
5.0 mmol) and Pd(OAc) (0.1 mmol, 10 mol%) in DMF (4.0 mL) at
20–125 8C under nitrogen atmosphere.
3
P (2.3 mmol), additive
(
2
1
b
c
GC yield.
Isolated yield.
3. Conclusion
In conclusion, a catalytic user-friendly palladium-cata-
lyzed phosphination using triarylphosphines as the
phosphinating reagents was developed and optimized.
This carbon–phosphorus bond formation was compatible
with a number of functional groups, including aldehyde,
keto, ester, nitrile, ether, pyridyl and thiothenyl group.
This phosphination utilizes the air-stable triphenyl-
phosphine as the phosphinating reagent and the reaction
were carried out in neutral media. This process has a great
potential to tailor a variety of substituted phosphines by
using different triarylphopshines with various functional-
ized aryl bromides.
product from B to C is feasible. A new equilibrium from
C–A –D would be established (Scheme 2). The trans-
0
complex D subsequently undergoes iodide dissociation and
reductive elimination with triphenylphosphine to produce
0
a phosphonium salt E and palladium complex A . Such
Pd-catalyzed phosphonium salt formation for meta- and
para- but not ortho-substituted aryl bromides has been
4
2
reported. Grushin et al. also reported that the iodide can
facilitate the Pd–aryl/P–aryl interchange through the
4
3
phosphonium salt pathway in the ArPdX(PPh ) complex.
3
2
a
Table 6. Palladium-catalyzed phosphination of aryl bromides with iodide salts
ð9Þ
b
Entry
1
Substrate
Product
Salt
KI
Time (h)
10
% Yield
60
2
4
4
2
3
NaI
KI
48
16
52
49
4
KI
12
42
9
a
Reaction conditions: ArBr (1.0 mmol), Ph
at 120–125 8C
Isolated yield.
3 2
P (2.3 mmol), Pd(OAc) (0.1 mmol, 10 mol%) and salt (5.0 mmol) in DMF (4.0 mL) under nitrogen atmosphere
b

5642
F. Y. Kwong et al. / Tetrahedron 60 (2004) 5635–5645
4. Experimental
flask. Evacuated and backfilled with nitrogen three times.
The Schenk flask was then added dry DMF (4.0 mL) under
nitrogen. The solution was heated to 120–125 8C for a
specified time in Tables 4 and 5. The reaction was cooled
down and DMF was removed under reduced pressure. The
residue was purified by column chromatography on silica
gel eluting with hexane/ethyl acetate to obtain the pure
product.
4
.1. General considerations
Unless otherwise noted, all reagents were purchased from
commercial suppliers and used without purification. Hexane
for chromatography was distilled from anhydrous calcium
chloride. N,N-Dimethylformamide was distilled from mag-
nesium sulfate under reduced pressure. Thin layer
chromatography was performed on Merck precoated silica
gel 60 F254 plates. Silica gel (Merck, 70–230 and 230–400
4
7
48
4.1.1. 4-(Diphenylphosphino)benzaldehyde (1). General
procedure
A
was followed. R ¼0.6 (hexane/ethyl
f
1
49 1
mesh) was used for column chromatography. H NMR
acetate¼10:1). Mp 75.5–77 8C (lit. 69–71 8C). H NMR
spectra were recorded on a Br u¨ ker DPX 300 (300 MHz)
spectrometer. Spectra were referenced internally to the
residual proton resonance in CDCl (d 7.26 ppm), or with
tetramethylsilane (TMS, d 0.00 ppm) as the internal
standard. Chemical shifts (d) were reported as part per
million (ppm) in d scale downfield from TMS. C NMR
spectra were recorded on a Br u¨ ker DPX 300 (75 MHz)
spectrometer and referenced to CDCl (d 77.00 ppm).
3
(300 MHz, CDCl ) d 7.32–7.43 (m, 12H), 7.80 (dd, 2H,
3
1
3
J¼8.1, 1.5 Hz), 10.00 (s, 1H); C NMR (75 MHz, CDCl ) d
3
128.8 (d, J ¼7.2 Hz), 129.3, 133.5 (d, J ¼18.3 Hz),
3
CP
CP
134.0 (d, J ¼20.0 Hz), 135.7 (d, J ¼10.4 Hz), 136.0,
CP
CP
3
1
CP 3
146.5 (d, J ¼15.5 Hz), 191.9; P (162 MHz, CDCl ) d
1
3
þ
23.41; MS (EI): m/z (relative intensity) 290 (M , 100), 261
(8), 211 (9), 183 (95), 165 (12), 152 (20).
3
1
P
NMR spectra were recorded on a Varian 400 (162 MHz)
and referenced to 85% H PO externally. Coupling
4.1.2. 4-(Diphenylphosphino)acetophenone (2).50 General
procedure
A
was followed. R ¼0.2 (hexane/ethyl
3
4
f
5
0 1
constants (J) were reported in Hertz (Hz). Mass spectra
EIMS and FABMS) were recorded on a HP 5989B Mass
acetate¼20:1). Mp 118–120 8C (lit. 119–120 8C).
H
(
NMR (300 MHz, CDCl ) d 2.57 (s, 3H), 7.29–7.38 (m,
3
1
3
Spectrometer. High resolution mass spectra (HRMS) were
obtained on a Br u¨ ker APEX 47e FT-ICR mass spectro-
meter (ESIMS). GC–MS analysis was conducted on a
HP G1800C GCD system using a HP5MS column
12H), 7.88 (dd, 2H, J¼8.3, 1.3 Hz); C NMR (75 MHz,
CDCl ) d 26.6, 127.9 (d, J ¼6.2 Hz), 128.6 (d, J
¼
¼
3
CP
CP
CP
7.2 Hz), 129.1, 133.2 (d, J ¼18.5 Hz), 133.9 (d, J
CP
19.9 Hz), 135.9 (d, J ¼10.4 Hz), 136.7, 144.3 (d,
CP
(
30 m£0.25 mm). The products described in GC yield
J ¼14.2 Hz), 197.8; MS (EI): m/z (relative intensity) 304
CP
þ
according to the authentic samples/anthracene calibration
curve.
(M , 100), 289 (10), 261 (12), 227 (11), 183 (90), 152 (30).
5
1
4
.1.3. Methyl 4-(diphenylphosphino)benzoate (3).
General procedure A: palladium-catalyzed phosphination
of aryl bromides in DMF. Aryl bromides (1.0 mmol),
triphenylphosphine (655 mg, 2.5 mmol) and Pd(OAc)2
General procedure A was followed. R ¼0.6 (hexane/ethyl
f
4
9 1
acetate¼10:1). Mp 103–105 8C (lit. 99–100 8C). H
NMR (300 MHz, CDCl ) d 7.28–7.38 (m, 12H), 7.97 (dd,
3
1
3
(
22.4 mg, 0.1 mmol, 10 mol%) were charged to a Teflon
2H, J¼8.4, 1.5 Hz); C NMR (75 MHz, CDCl ) d 52.2,
3
screw-capped Schlenk flask. Evacuated and backfilled with
nitrogen three times. The Schenk flask was then added dry
DMF (4.0 mL) under nitrogen. The solution was heated to
128.7 (d, J ¼7.1 Hz), 129.1, 129.3 (d, J ¼6.4 Hz), 133.0,
CP
CP
133.1 (d, J ¼18.5), 133.9 (d, J ¼19.9 Hz), 136.1 (d,
CP
CP
J ¼10.5 Hz), 144.0 (d, J ¼14.0 Hz), 166.9; MS (EI): m/z
CP
CP
þ
1
10–115 8C for a specified time in Table 1 and generally the
(relative intensity) 320 (M , 100), 289 (8), 261 (7), 207 (9),
183 (70), 166 (12).
color of the solution changed from yellow to red. The
reaction was cooled down and DMF was removed under
reduced pressure. The residue was purified by column
chromatography on silica gel eluting with hexane/ethyl
acetate to obtain the pure product.
52
4.1.4. 4-(Diphenylphosphino)benzonitrile (4). General
procedure A was followed. R ¼0.6 (hexane/ethyl acetate ¼
f
4
9 1
10:1). Mp 86–87 8C (lit. 86–87 8C). H NMR (300 MHz,
CDCl ) d 7.28–7.39 (m, 12H), 7.57 (dd, 2H, J¼8.4,
3
1
3
General procedure B: palladium-catalyzed phosphination
of aryl bromides under solventless conditions. Aryl
bromides (1.0 mmol), triphenylphosphine (603 mg,
1.2 Hz); C NMR (75 MHz, CDCl ) d 111.8, 118.9, 128.8
3
(d, J ¼7.4 Hz), 129.5, 131.7 (d, J ¼5.9 Hz), 133.4 (d,
CP
CP
J ¼18.4 Hz), 134.0 (d, J ¼20.2 Hz), 135.3 (d, J
¼
CP
CP
CP
2
.3 mmol) and Pd(OAc) (22.4 mg, 0.1 mmol, 10 mol%)
2
10.3 Hz), 145.1 (d, J ¼16.5 Hz); MS (EI): m/z (relative
CP
þ
were charged to a Teflon screw-capped Schlenk flask.
Evacuated and backfilled with nitrogen three cycles. The
solution was heated to 115 8C for a specified time in Table 3.
The reaction was cooled down and dichloromethane was
added. The residue was purified by column chromatography
on silica gel eluting with hexane/ethyl acetate to obtain the
pure product.
intensity) 287 (M , 100), 208 (55), 195 (8), 183 (62), 177
(12).
4.1.5. 4-(Diphenylphosphino)anisole (5).53 General pro-
cedure A was followed. Mp 64.5–65.5 8C (lit. 63–
5
0b 1
65 8C).
H NMR (300 MHz, CDCl ) d 3.69 (s, 3H),
3
7.10 (dd, 2H, J¼8.1, 4.0 Hz), 7.24–7.59 (m, 12H); MS (EI):
þ
m/z (relative intensity) 292 (M , 100), 277 (12), 259 (10),
215 (30), 183 (48).
General procedure C: palladium-catalyzed phosphination
of aryl bromides in the presence of salts. Aryl bromides
(
1.0 mmol), triphenylphosphine (603 mg, 2.3 mmol),
Pd(OAc)2 (22.4 mg, 0.1 mmol, 10 mol%) and salt
5.0 mmol) were charged to a Teflon screw-capped Schlenk
4.1.6. 3-(Diphenylphosphino)anisole (9).54 General pro-
cedure A was followed. R ¼0.4 (hexane/ethyl acetate ¼
f
1
(
20:1); H NMR (300 MHz, CDCl ) d 3.71 (s, 3H),
3

F. Y. Kwong et al. / Tetrahedron 60 (2004) 5635–5645
5643
1
3
6
(
1
1
.83–6.90 (m, 3H), 7.22–7.34 (m, 11H); C NMR
(120 mg, 33%) as pale yellow solid after purified by column
chromatography on silica gel using a solvent mixture
75 MHz, CDCl ) d 55.1, 114.3, 118.9 (d, J ¼21.1 Hz),
3
CP
26.0 (d, J ¼18.8 Hz), 128.5 (d, J ¼6.8 Hz), 128.7,
(hexane/ethyl acetate¼10:1) as the eluent. R ¼0.2 (hexane/
CP
CP
f
1
29.5 (d, J ¼7.7 Hz), 133.7 (d, J ¼19.4 Hz), 137.0 (d,
ethyl acetate¼10:1). Mp 54–56 8C; H NMR (300 MHz,
CP
CP
J ¼10.6 Hz), 138.7 (d, J ¼11.0 Hz), 159.5 (d, J
¼
CDCl ) d 2.57 (s, 3H), 3.81 (s, 6H), 6.90 (dd, 4H, J¼6.0,
CP
CP
CP
3
3
1
8.3 Hz); P NMR (162 MHz, CDCl ) d 23.81; MS (EI):
m/z (relative intensity) 292 (M , 100), 213 (22), 199 (20),
2.1 Hz), 7.25–7.32 (m, 6H), 7.85 (dd, 2H, J¼8.4, 1.5 Hz);
3
þ
13
C NMR (75 MHz, CDCl ) d 26.6, 55.2, 114.3 (d, J
3
¼
CP
1
83 (48).
8.3 Hz), 127.1 (d, J ¼7.4 Hz), 127.8 (d, J ¼5.8 Hz),
CP
CP
1
32.6 (d, J ¼17.7 Hz), 135.5 (d, J ¼21.5 Hz), 136.3,
CP
CP
31
5
5
4
procedure
.1.7. 3-(Diphenylphosphino)pyridine (11).
A
General
was followed. R ¼0.8 (hexane/ethyl
146.1 (d, J ¼13.9 Hz), 160.5, 197.8; P NMR (162 MHz,
CP
CDCl ) d 213.03; MS (EI): m/z (relative intensity) 364
3
f
1
þ
214 (40), 199 (18); HRMS (ESIMS) calcd for
acetate¼5:1); H NMR (300 MHz, CDCl ) d 8.34 (d, 1H,
(M , 100), 349 (10), 281 (9), 257 (10), 245 (30), 229 (8),
3
J¼1.4 Hz), 8.30 (d, 1H, J¼8.3 Hz), 7.92 (t, 1H, J¼8.2 Hz),
þ
7
.27–7.69 (m, 11H); MS (EI): m/z (relative intensity) 263
C H O PH 365.1307, found 365.1289.
22 21 3
þ
(
M , 100), 186 (20).
5
6
4
.1.11. 3-(Diphenylphosphino)benzaldehyde (17).
4
.1.8. 4-(Di(4-tolyl)phosphino)acetophenone (14). General
procedure A was followed. 4-Bromoacetophenone (199 mg,
.0 mmol), palladium(II) acetate (22.4 mg, 0.1 mmol), tri(4-
General procedure B was followed. R ¼0.6 (hexane/ethyl
f
1
acetate¼10:1); H NMR (300 MHz, CDCl ) d 7.32–7.43
3
1
3
1
(m, 12H), 7.80 (dd, 2H, J¼8.1, 1.5 Hz), 10.00 (s, 1H);
C
tolyl)phosphine (699 mg, 2.3 mmol) and dry DMF (4 mL)
were used to obtain 4-(di(4-tolyl)phosphino)acetophenone
NMR (75 MHz, CDCl ) d 128.8 (d, J ¼7.2 Hz), 129.3,
3
CP
133.5 (d, J ¼18.3 Hz), 134.0 (d, J ¼20.0 Hz), 135.7 (d,
CP CP
3
1
(
14) (129 mg, 39%) as light yellow solid after purified by
column chromatography on silica gel using a solvent
J ¼10.4 Hz), 136.0, 146.5 (d, J ¼15.5 Hz), 191.9;
P
(162 MHz, CDCl ) d 23.41; MS (EI): m/z (relative
CP
CP
3
þ
mixture (hexane/ethyl acetate¼10:1) as the eluent. R ¼0.4
intensity) 290 (M , 100), 261 (8), 211 (9), 183 (95), 165
(12), 152 (20).
f
1
(
hexane/ethyl acetate¼10:1). Mp 58–60 8C; H NMR
(
300 MHz, CDCl ) d 2.35 (s, 6H), 2.57 (s, 3H), 7.15–7.25
3
(
1
m, 8H), 7.36 (dd, 2H, J¼8.4, 1.5 Hz), 7.86 (dd, 2H, J¼8.4,
1
3
.5 Hz); C NMR (75 MHz, CDCl ) d 21.3, 26.6, 127.9
3
Acknowledgements
(
9
1
d, J ¼6.0 Hz), 129.5 (d, J ¼7.5 Hz), 132.7 (d, J
¼
CP
CP
CP
.0 Hz), 133.0 (d, J ¼18.2 Hz), 134.0 (d, J ¼20.3 Hz),
CP
CP
CP
The work described in this paper was supported by the Area
of Excellence Scheme established under the University
Grants Committee of the Hong Kong Special Adminis-
trative Region, Hong Kong, China, (Project No. [AoE/P-
3
1
36.5, 139.2, 145.3 (d, J ¼14.3 Hz), 197.8; P NMR
(
intensity) 332 (M , 100), 317 (5), 289 (10), 281 (7), 241
162 MHz, CDCl ) d 212.60; MS (EI): m/z (relative
3
þ
8), 211 (30), 197 (28); HRMS (ESIMS) calcd for
(
C H OPH 333.1408, found 333.1385.
10/01]).
þ
2
2 21
4.1.9. 4-(Bis(3,5-dimethylphenyl)phosphino)aceto-
phenone (15). General procedure A was followed. 4-Bromo-
References and notes
acetophenone (199 mg, 1.0 mmol), palladium(II) acetate
22.4 mg, 0.1 mmol), trixylylphosphine (796 mg, 2.3 mmol)
and dry DMF (4 mL) were used to yield 4-(bis(3,5-
dimethyl)phosphino)acetophenone (15) (122 mg, 34%) as
pale yellow solid after purified by column chromatography
on silica gel using a solvent mixture (hexane/ethyl
(
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6
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