Selective catch and release of a synthetically useful phosphine ligand

Article abstract of DOI:10.1016/j.tetlet.2003.07.004

The selective catch and release of the synthetically useful (o-biphenyl)(t-butyl)₂P from basic and non basic compounds, utilizing solid phase supported sulfonic acid sources is demonstrated.

Full text of DOI:10.1016/j.tetlet.2003.07.004

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7537–7540
Selective catch and release of a synthetically useful phosphine
ligand
Jennifer L. Marugg, Martin L. Neitzel* and John Tucker*
Elan Pharmaceuticals, South San Francisco, CA 94080, USA
Received 19 June 2003; revised 30 July 2003; accepted 31 July 2003
Abstract—The selective catch and release of the synthetically useful (o-biphenyl)(t-butyl)2P from basic and non basic compounds,
utilizing solid phase supported sulfonic acid sources is demonstrated.
© 2003 Elsevier Ltd. All rights reserved.
The synthetic versatility of sterically hindered alkyl
phosphine ligands in palladium-catalyzed reactions
has been the focus of several recent publications.1
Chromatography has been used to isolate the prod-
ucts and recycle the costly phosphine ligand, thus
making these reactions impractical for a solution
phase parallel synthesis protocol. Upon performing
catch and release purification on synthesis products
containing basic functionality, it was observed that
(o-biphenyl)(t-butyl)2P ligand 1 in the reaction mix-
ture was also effectively scavenged by the polystyrene
bound sulfonic acid. It occurred to us that selective
catch and release of phosphine 1 from the synthesis
products would offer a convenient method for paral-
lel purifications as well as a means of ligand recy-
cling. Herein, we describe the selective catch and
release of the (o-biphenyl)(t-butyl)2P ligand 1 from
other compounds and synthesis products.
such reactions. Phosphine 1 was effectively scavenged
using 2% cross-linked polystyrene bound sulfonic
acid,2 or Silicycle® sulfonic acid functionalized silica
gel in a variety of solvents (Table 1). All of these
experiments were performed open to air. Phosphine 1
was completely scavenged with a minimum of 2.0
equiv. of silica supported sulfonic acid, while only 1.6
equiv. was needed for complete capture with
polystyrene bound sulfonic acid (Table 1, entries 1
and 3). Similar conditions failed to capture
triphenylphosphine (Table 1, entries 2 and 4). These
results can be understood in terms of the greater
basicity of 1 compared to triphenylphosphine.3 While
phosphine 1 was completely captured on polystyrene
bound sulfonic acid resin when methanol or DME
was used as the solvent (Table 1, entries 3 and 5),
incomplete capture was observed in THF, DCM and
DMF (Table 1, entries 9–11), and no apparent cap-
ture was observed when ethyl acetate, dioxane, or
diethyl ether was used as solvent (Table 1, entries
6–8). These results are probably best explained by the
increased ability of methanol and DME to swell the
highly polar resin. Although phosphine 1 showed
only partial capture on silica based solid support sul-
fonic acid when DMF was used as solvent (Table 1,
entry 18), complete capture was achieved with DME,
ethyl acetate, dioxane, diethyl ether, THF, and DCM
(Table 1, entries 12–17). Therefore, the Silicycle® sul-
fonic acid functionalized silica is a versatile solid sup-
port for catch and release of phosphine 1 due to its
extensive solvent compatibility.
Reaction solvent can be an important component in
palladium-catalyzed reaction optimization, therefore, a
systematic study of solvent compatibility was under-
taken to assess the usefulness of this catch and
release methodology with solvents commonly used for
The selective capture of compounds with a broad
variety of basic functionality and phosphine 1 was
* Corresponding authors.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.07.004

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J. L. Marugg et al. / Tetrahedron Letters 44 (2003) 7537–7540
Table 1. Solvent effects on scavenging of phosphines with solid phase supported sulfonic acid
Entry
Phosphine
Solvent
Sulfonic acid support
Sulfonic acid (equiv.)
Phosphine scavengeda
1
2
3
4
5
6
7
8
1
MeOH
MeOH
MeOH
MeOH
DME
EtOAc
Dioxane
Ether
Silica
Silica
2.0b
2.5
1.6b
2.5
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
Yes
No
Yes
No
Yes
No
No
Ph3P
1
Ph3P
Polystyrene
Polystyrene
Polystyrene
Polystyrene
Polystyrene
Polystyrene
Polystyrene
Polystyrene
Polystyrene
Silica
Silica
Silica
Silica
Silica
Silica
Silica
1
1
1
1
1
1
1
1
1
1
1
1
1
1
No
9
THF
DCM
DMF
60%c
80%c
80%c
Yes
Yes
Yes
Yes
Yes
Yes
40%c
10
11
12
13
14
15
16
17
18
DME
EtOAc
Dioxane
Ether
THF
DCM
DMF
a The phosphine solution (0.1 M) was agitated with sulfonic acid resin for 15 min, the mixture was filtered, and the resin was washed with the
same solvent. The combined filtrate and wash was analysed by LC-MS. ‘Yes’ denotes complete capture (<2% remaining) by LC-MS as compared
to biphenyl internal standard, ‘No’ denotes no noticeable change in compound peak compared to biphenyl internal UV standard.
b Experimentally determined effective minimum equiv. of solid phase supported sulfonic acid for complete capture.
c Approximate percentage of phosphine scavenged relative to a biphenyl internal UV standard as determined by LC-MS.
achieved with 3 equiv. of either polystyrene or silica
supported sulfonic acid in methanol (Table 2). The two
supports gave identical results in these examples. Com-
plete capture was achieved for amines 2, 3, and 4 while
leaving phosphine 1 in solution (Table 2, entries 1–3).
Subsequent release of compounds 2, 3, and 4 with 2.0
M methanolic ammonia resulted in 83, 74, and 78%
recovery, respectively, with no detectable contamina-
tion of phosphine 1 (Table 2, entries 1–3). Three equiv.
of solid supported sulfonic acid failed to capture diary-
lamine 5, however, phosphine 1 was preferentially scav-
enged from the mixture (Table 2, entry 4). Treatment of
the sulfonic acid support with 2.0 M methanolic ammo-
nia recovered phosphine 1 without detection of diaryl-
amine 5 (Table 2, entry 4). Three equiv. of solid sup-
ported sulfonic acid affected the partial capture of
aniline 6 and pyrazole 7 along with partial capture of
phosphine 1 (Table 2, entries 5 and 6). This result
prompted us to increase the amount of sulfonic acid
and investigate conditions for selective release.
compound 5 remained in solution. No difference was
observed between silica and polystyrene sulfonic acid
source in all instances. Selective release of phosphine 1
from amines 2, 3, and 4, was achieved with 30%
pyridine in methanol, with each resulting phosphine
solution containing no detectable amount of amines 2,
3, or 4 (Table 3, entries 1–3). Subsequent treatment of
the solid support with 2.0 M methanolic ammonia
liberated amines 2, 3, and 4 with no detectable phos-
phine contaminant (Table 3, entries 1–3). Aniline 6 and
pyrazole 7 were selectively released from the solid sup-
port with 5% pyridine in methanol and were uncontam-
inated with phosphine 1 (Table 3, entries 5 and 6).
Complete release of phosphine 1 was then achieved
with 2.0 M methanolic ammonia, and compounds 6
and 7 were not detectable in the phosphine solution.
A Suzuki4 reaction between a 3-chloropyridine and
phenylboronic acid was performed to highlight the
utility of this catch and release methodology in a
common cross-coupling reaction (Eq. (1)). In such a
reaction, the desired product would typically be isolated
by aqueous work-up and chromatography. Instead,
Six equiv. of solid supported sulfonic acid in methanol
was sufficient to effect the complete capture of com-
pounds 2, 3, 4, 6, and 7 as well as phosphine 1, while
(1)

J. L. Marugg et al. / Tetrahedron Letters 44 (2003) 7537–7540
Table 2. Selective capture with 3 equiv. of solid supported sulfonic acida
7539
upon reaction completion, the addition of a 6-fold
excess of Silicycle® sulfonic acid functionalized silica gel
to the reaction mixture effectively captured both the
desired product and phosphine 1. The choice of the
sulfonic acid functionalized silica gel was due to the
fact that the reaction was performed in THF. After
filtration, treatment of the solid support with 5% pyri-
dine in methanol was sufficient to cleave the desired
product which was obtained in 88% yield with
no phosphine impurity. Subsequent treatment of
the solid support with 2.0 M methanolic ammonia
liberated phosphine 1 with 71% recovery. The entire
reaction workup procedure was performed open to air,
as the phosphine ligand is fairly resistant to air oxida-
tion.
mixture, as well as for the recovery of the ligand for
future use.
In summary, we have demonstrated the effectiveness of
using 2% cross-linked polystyrene sulfonic acid resin
and Silicycle® sulfonic acid functionalized silica gel in
the separate catch and selective release of (o-
biphenyl)(t-butyl)2P from various basic and non basic
compounds. In addition, we have demonstrated the
usefulness of this catch and release methodology in a
cross-coupling reaction in which the product and the
phosphine may be captured and each selectively liber-
ated. This novel catch and release methodology is a
potentially powerful procedure for purifications of pal-
ladium catalyzed reactions in addition to a convenient
alternative to conventional ligand recycling techniques.
Investigations to expand the scope of this methodology
will be reported in due course.
This procedure5 proved to be a convenient method for
the isolation of the desired product from the reaction

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J. L. Marugg et al. / Tetrahedron Letters 44 (2003) 7537–7540
Table 3. Selective catch and release with 6 equiv. of solid supported sulfonic acida
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