Synthesis of water-soluble phosphine oxides by Pd/C-catalyzed P-C coupling in water

Article abstract of DOI:10.1021/ol300582y

Cross-coupling between diphenylphosphine oxide and halogenated benzoic acids catalyzed by Pd/C in water is a green, simple, and fast protocol to obtain water-soluble tertiary phosphine oxides without the addition of ligands and additives. Low reaction times and microwave irradiation make this method general and excellent for laboratory and large-scale synthesis without the need to use organic solvents in reactions and workup.

Full text of DOI:10.1021/ol300582y

ORGANIC
LETTERS
2012
Vol. 14, No. 8
2188–2190
Synthesis of Water-Soluble Phosphine
Oxides by Pd/C-Catalyzed PÀC Coupling
in Water
Stephan M. Rummelt,†,‡ Marco Ranocchiari,*,‡ and Jeroen A. van Bokhoven†,‡
ETH Zurich, Department of Chemistry and Applied Biosciences, 8093 Zu€rich,
Switzerland, and Paul Scherrer Institute, Department of Synchrotron Radiation and
Nanotechnology, CH-5232 Villigen PSI, Swizterland
marco.ranocchiari@psi.ch
Received March 7, 2012
ABSTRACT
Cross-coupling between diphenylphosphine oxide and halogenated benzoic acids catalyzed by Pd/C in water is a green, simple, and fast protocol
to obtain water-soluble tertiary phosphine oxides without the addition of ligands and additives. Low reaction times and microwave irradiation
make this method general and excellent for laboratory and large-scale synthesis without the need to use organic solvents in reactions and workup.
Phosphine oxides are important intermediates for che-
mical synthesis because they are precursors to free phos-
phines, which are essential for transition metal catalysis1
and for organocatalysis.2 They can also be excellent
ligands3 and have found application in organocatalysis
based on their Lewis basic properties.4 Water-soluble
phosphines and phosphine oxides have special advantages
in industrial processes based on homogeneous catalysts
since they allow easier separation of the metal catalyst
from the reaction mixture by using two-phase water/
organic solvent systems.5 The SHELL Higher Olefinic
Process (SHOP) is a practical industrial example of a
successful application of water-soluble phosphines in
two-phase homogeneous catalysis.6
The introduction of polar groups, such as sulphates,
ammonium salts, and carboxylates, to organophosphor-
ous compounds is however strongly limited by the few
methods available in the literature, which usually require
either harsh conditions or the use of air-sensitive reagents in
stoichiometric amounts.5a Catalytic processes that build
phosphorusÀcarbon bonds (PÀC coupling)7 based on
Pd,8 Cu,9 and Ni10 overcome some of these limitations
and allow the synthesis of phosphines under mild conditions
† ETH Zurich.
‡ Paul Scherrer Institute.
(1) (a) Van Leeuwen, P. W. N. M. Homogeneous Catalysis; Kluwer
Academic Publishers: Dordrecht, The Netherlands, 2004.
(2) (a) Morimoto, H.; Yoshino, T.; Yukawa, T.; Lu, G.; Matsunaga,
S.; Shibasaki, M. Angew. Chem., Int. Ed. 2008, 47, 9125. (b) Lu, X.;
Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535.
(3) (a) Abu-Gnim, C.; Amer, I. J. Chem. Soc., Chem. Commun. 1994,
115. (b) Abu-Gnim, C.; Amer, I. J. Organomet. Chem. 1996, 516, 235.
(c) Daikai, K.; Kamaura, M.; Inanaga, J. Tetrahedron Lett. 1998, 39,
7321. (d) Fronczek, F. R.; Luck, R. L.; Wang, G. Inorg. Chem. Commun.
2002, 5, 384. (e) Fawcett, J.; Platt, A. W. G.; Russell, D. R. Polyhedron
2002, 21, 287. (f) Zhu, D.; Xu, L.; Wu, F.; Wan, B. Tetrahedron Lett.
2006, 47, 5781. (g) Denmark, S. E.; Smith, R. C.; Tymonko, S. A.
Tetrahedron 2007, 63, 5730. (h) Morimoto, H.; Yoshino, T.; Yukawa, T.;
Lu, G.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2008, 47,
9125. (i) He, L. P.; Mu, H. L.; Li, B. X.; Li, Y. S. J. Polym. Sci., Polym.
Chem. 2010, 48, 311.
(6) Keim, W. Chem. Ing. Tech. 1984, 56, 850.
(7) (a) Beletskaya, I. P.; Kazankova, M. A. Russ. J. Org. Chem. 2002,
38, 1391. (b) Schwan, A. L. Chem. Soc. Rev. 2004, 33, 218. (c) Tappe, F.;
Trepohl, V.; Oestreich, M. Synthesis 2010, 3037. (d) Glueck, D. S. Top.
Organomet. Chem. 2010, 31, 65.
(8) (a) Herd, O.; Hessler, A.; Hingst, M.; Tepper, M.; Stelzer, O.
J. Organomet. Chem. 1996, 522, 69. (b) Herd, O.; Hessler, A.; Hingst, A.;
Machnitzki, P.; Tepper, M.; Stelzer, O. Catal. Today 1998, 42, 413. (c)
Brauer, D. J.; Hingst, M.; Kottsieper, K. W.; Liek, C.; Nickel, T.;
Tepper, M.; Stelzer, O.; Sheldrick, W. S. J. Organomet. Chem. 2002,
645, 14.
(4) Benaglia, M.; Rossi, S. Org. Biomol. Chem. 2010, 8, 3824.
(5) (a) Herrmann, W. A.; Kohlpaintner, C. W. Angew. Chem., Int.
Ed. Engl. 1993, 32, 1524. (b) Pinault, N.; Bruce, D. W. Coord. Chem. Rev.
2003, 241, 1. (c) Shaughnessy, K. H. Chem. Rev. 2009, 109, 643.
(9) (a) Gelman, D.; Jiang, L.; Buchwald, S. L. Org. Lett. 2003, 5,
2315. (b) Van Allen, D.; Venkataraman, D. J. Org. Chem. 2003, 68, 4590.
(10) Cai, D.; Payack, J. F.; Bender, D. R.; Hughes, D. L.; Verhoeven,
T. R.; Reider, P. J. J. Org. Chem. 1994, 59, 7180.
r
10.1021/ol300582y
Published on Web 03/30/2012
2012 American Chemical Society

and with great functional group tolerance. Still, PÀC
coupling reactions are mostly homogeneous systems that
need (a) the presence of ligands that are able to activate
bromo or possibly chloroaryl/allyl derivatives, (b) the use of
high boiling organic solvents, (c) generally secondary phos-
phines as coupling partners, which are oxygen-sensitive
reactants, and (d) quite long reaction times up to 48 h to
give good conversion. For the reasons mentioned above,
PÀC couplings are still limited even though they present
major advantages over traditional stoichiometric methods.
A catalytic method of industrial applicability that pro-
duces water-soluble phosphine derivatives should ideally
be (a) insensitive to air, (b) recyclable, (c) sustainable from
an environmental point of view, (d) versatile, and (e)
potentially scalable. We present here a method to achieve
PÀC coupling with such characteristics. This method
produces water-soluble phosphine oxides with carboxylic
acid groups by employing diphenlyphosphine oxide as the
P-source and Pd/C as the catalyst. Since our interest is to
produce water-soluble phosphorus compounds, H2O is the
obvious choice as the reaction medium for both reaction
and workup. Sustainability and nontoxicity are key points
for this new evironmentally friendly process.
Secondary phosphine oxides are known to react with
bromo aryls, allyls, and aryltriflates in the presence of a
Pd,11 Ni,10 or Cu12 source and a base in organic solvents.
Recently, Zhang et al. published a PÀC coupling of a
bromo- and iodoaryl with diphenylphosphine oxide
(HP(O)Ph2) in water using a nickel/zinc homogeneous
system.13 No heterogeneous catalytic systems that produce
phosphine oxides from PÀC coupling are known, to the
best of our knowledge.
An initial screening was performed with 4-iodobenzoic
acid, which was used as a model reactant for coupling with
diphenylphosphine oxide catalyzed by Pd/C in water using
conventional heating. The screening results of tempera-
ture, different bases, phase-transfer additives, and time are
shown in Table 1.
Table 1. Initial Screening of PÀC Coupling of 4-Iodobenzoic
Acid under Conventional Heatinga
Pd/C
HP(O)Ph2
(equiv)
base
TBAB
conversion
(%)
entry (mol %)
(mol %)
(equiv)
1
5.0
5.0
5.0
5.0
5.0
0.20
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.3
1.3
Na2CO3
(6 equiv)
Na2CO3
(6 equiv)
Et3N
1.0
1.0
1.0
1.0
1.0
1.0
1.0
À
62
0
2b
3
58
80
85
44
87
98
99
(6 equiv)
NaOH
4
(6 equiv)
K2CO3
5
(6 equiv)
K2CO3
6
(6 equiv)
K2CO3
7
(6 equiv)
K2CO3
8
(6 equiv)
K2CO3
9c
À
(4 equiv)
a Standard conditions: iodobenzoic acid (0.55 mmol), HP(O)Ph2,
base, Pd/C, H2O (10 mL), conventional heating, 100 °C, 1 h. b Reaction
temperature: 70 °C. c H2O (5 mL).
filtration over Celite of the catalyst, the filtrate was simply
acidified with HCl (∼1 M), and the product was recovered
by filtration. No organic solvent was used.
Different halogenated benzoic acids (4-bromo and 2-
iodobenzoic acid) did not yield the desired product under
conventional heating. This limited the scope of the reac-
tion. We therefore used microwave (MW) heating, instead
of conventional heating, inspired by the results of Stadler
et al. in the case of PÀC coupling with diphenylphos-
phine.14 Figure 1 summarizes different substrates and
their yields.
Simple iodo- and bromobenzoic acids such as 3- and
4-bromobenzoic acid (1a and 2a) and 3- and 4-iodobenzoic
acid (1b and 2b) readily coupled with HP(O)Ph2 in high
yields at 180 °C under MW irradiation, to give phosphine
oxides7 and 8. Iodo derivatives yielded less product, due to
their easier tendency to dehalogenate under reaction con-
ditions as observed in other similar protocols.15,11c Traces
of benzoic acid were observed via 1H NMR spectroscopy
of the crude reaction mixture. 4-Chlorobenzoic acid also
coupled with HP(O)Ph2, although in 18% yield.
Whenthereaction was performedattemperaturesbelow
100 °C, no conversion was observed (entry 2). The base
had a strong influence on the conversion, and K2CO3 was
found to be best among Na2CO3, NaOH, and Et3N
(entries 1 and 3À5). Although initial screening was per-
formed in the presence of a phase transfer agent such as
tetra-butylammonium bromide (TBAB), we discovered
that it did not have any positive effects on the reaction
(entries 8, 9). Furthermore, a slight excess of HP(O)Ph2
was needed to obtain full conversion (entries 8, 9). Under
optimized conditions, 4-iodobenzoic acid (0.55 mmol) was
dissolved in degassed water (5 mL) with Pd/C (1 mol %),
K2CO3 (2.2 mmol), and HP(O)Ph2 (0.72 mmol), and the
mixture was stirred at 100 °C for 1 h (entry 9). After
Commercially available 3-bromo-4-methylbenzoic acid
(3a) and 3-iodo-4-methylbenzoic acid (3b) gave the corre-
sponding novel phosphine oxide 9 in 60% and 81%
yield, respectively. Phosphine oxide 10 was produced in
moderate yield from 3-bromo-4-methoxybenzoic (4a) and
(11) (a) Xu, Y.; Li, Z.; Xia, J.; Guo, H.; Huang, Y. Synthesis 1984,
781. (b) Xu, Y.; Xia, J.; Guo, H. Synthesis 1986, 691. (b) Kurz, L.; Lee,
G.; Morgans, D., Jr.; Waldyke, M. J.; Ward, T. Tetrahedron Lett. 1990,
131, 6321.
(12) McDougal, N. T.; Streuff, J.; Mukherjee, H.; Virgil, S. C.; Stoltz,
B. M. Tetrahedron Lett. 2010, 51, 5550.
(13) Zhang, X.; Liu, H.; Hu, X.; Tang, G.; Zhu, J.; Zhao, Y. Org.
(14) Stadler, A.; Kappe, C. O. Org. Lett. 2002, 4, 3541.
Lett. 2011, 13, 3478.
(15) Murata, M.; Buchwald, S. L. Tetrahedron 2004, 60, 7397.
Org. Lett., Vol. 14, No. 8, 2012
2189

the product precipitated, whereas diphenylphosphonic
acid, residual starting material, and dehalogenated pro-
duct remained in solution. Alternatively, starting material
and dehalogenation product were removed from the pre-
cipitate by sublimation. Besides 12, which was recrystal-
lized in ethanol/water, all the phosphine oxides herein
reported could be isolated with >95% purity17 without
the employment of organic solvents.
We also tested the recyclability of the catalyst for the
phosphination of substrate 3b. After the first run, the
catalyst was filtered with a microfiber glass filter and
reused at 180 °C under MW irradiation. The second
catalyst run produced 9 in 78% yield, comparable to the
first run. Pd/C as recyclable catalyst for PÀC coupling is
not unprecedented,14,18 and its catalytic activity is presum-
ably due to microwaves, which create electric discharge or
hot spots within the heterogeneous catalyst and are able to
create small and locally superheated, highly active sites.
This phenomenon has been observed and studied only in
CÀC coupling,19 but analogous assumptions can be made
for the PÀC one.
We have developed a novel method to couple various
iodo- and bromobenzoic acids with diphenylphosphine
oxide in water, by using a heterogeneous and recyclable
catalyst. Because of the utilization of (a) water as solvent
for both reaction and workup, (b) a heterogeneous
catalyst, and (c) microwave irradiation, it is an environ-
mentally friendly and sustainable reaction for carbonÀ
phosphorus coupling. This protocol allows the synthesis of
four new phosphine oxides. The corresponding free phos-
phines containing carboxylic acid functionalities can be
synthesized by reduction with trichlorosilane as previously
described.20 All the products were fully characterized and
can be of further use as ligands for biphasic and water-
soluble metal catalysis and organocatalysis. This, in com-
bination with the easy, fast reaction, simple workup, and
high purity of the desired compound, makes this reaction
protocol a good candidate for application in both labora-
tory and large-scale synthesis.
Figure 1. PÀC coupling of several halogenated benzoic acids
under MW heating. Standard conditions: halogenated benzoic
acid (1.1 mmol), HP(O)Ph2 (1.4 mmol), K2CO3 (4.4 mmol),
Pd/C (0.011 mmol), H2O (10 mL), MW irradiation, 180 °C, 1 h.
3-iodo-4-methoxybenzoic acid (4b). 1H NMR spectro-
scopic analysis of the reaction mixture revealed that the
moderate yield was due to dehalogenation in the case of
4b15,11c and due to both low conversion and dehalogena-
tion in the case of 4a. The novel phosphine oxide-amino
(11) and bis(phosphine oxide) (12) compounds were also
synthesized in 41% and 74% yield, respectively, from
commercially available starting materials 5 and 6. All
substrates with a halogen in the 2-position gave only traces
of product due to steric hindrance. Halogenated hydroxy-
benzoic acids gave only traces of product under the given
reaction conditions.
The workup was performed by filtration over Celite of
the catalyst, acidification, and filtration of the product, as
described above. 31P and 1H NMR spectroscopy analysis
of the crude reaction mixture revealed the presence of a
phosphorus-containing byproduct, which was identified as
diphenylphosphinic acid.16 Nevertheless, sucha byproduct
was easily removed by acidification of the reaction mixture
at controlled pH between 4 and 5. Under such conditions,
Acknowledgment. This work was supported by the
Laboratory for Catalysis and Sustainable Chemistry
(LSK) at Paul Scherrer Institute, Villigen, Switzerland
and by ETH Zurich, Switzerland.
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(16) Kalec, M.; Stawinski, J. Tetrahedron 2009, 65, 10406.
(17) Measured by 1H NMR spectroscopy.
(20) (a) Schiemenz, G. P.; Siebeneick, H. U. Chem. Ber. 1969, 102,
1883. (b) Kessler, P.; Kotzybahibert, F.; Leonetti, M.; Bouet, F.;
Ringler, P.;Brisson, A.;Menez, A.;Goeldner, M. P.;Hirth, C.Bioconjugate
Chem. 1994, 5, 199.
(18) (a) Lai, C. W.; Kwong, F. Y.; Wang, Y. C.; Chan, K. S.
Tetrahedron Lett. 2001, 42, 4883. (b) Wang, Y.; Lai, C. W.; Kwong,
F. Y.; Jia, W.; Chan, K. S. Tetrahedron 2004, 60, 9433.
(19) Horikoshi, S.; Osawa, A.; Abe, M.; Serpone, N. J. Phys. Chem.
C 2011, 115, 23030.
The authors declare no competing financial interest.
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